9857230|t|Cytotoxicity of Fas ligand against lymphoma cells with radiation-induced Fas antigen.
9857230|a|Fas antigen, also termed APO-1 or CD95, is a transmembrane protein and a member of the tumor necrosis factor receptor/nerve growth factor receptor superfamily which mediates apoptosis upon oligomerization. The Fas/Fas ligand system is considered to be a key regulator of apoptosis. Recently, we have demonstrated that Fas antigen expression is induced by low-dose irradiation of some types of lymphomas, and we also demonstrated that irradiation-induced Fas antigen expression increased with the passage of time until peaking at 48 h after irradiation in CML-C1, CML-C2, DL-40, and DL-95 cell lines. In this study, we also examined the potential cytotoxicity of Fas ligand peptide against several types of lymphoma/leukemia cell lines that showed induction of Fas antigen expression under irradiation. Flow cytometry analysis was performed at 6, 24 and 48 h after irradiation. Samples (1 x10(6) cells/ml) from irradiated and non-irradiated cells of each cell line were incubated with or without 5 microg/ml of Fas ligand peptide for 2 h at 37 degrees C in a humidified atmosphere of 5% carbon dioxide (CO2) in air. The killing effect of Fas ligand against cell lines of CML-C1, DL-40, and DL-95 were clearly identified as the percentage of cells with Fas antigen expression induced by irradiation. Concerning HD-70 cell line, for which soluble Fas antigen has been identified, the killing effects were clearly observed in samples pre-treated with PBS washings. To our knowledge, this is the first report describing a possible application of the Fas/Fas ligand system in treatment of certain types of malignancies in which Fas antigen is inducible by irradiation.
9857230	16	26	Fas ligand	Gene	356
9857230	73	84	Fas antigen	Gene	355
9857230	86	97	Fas antigen	Gene	355
9857230	111	116	APO-1	Gene	355
9857230	120	124	CD95	Gene	355
9857230	296	299	Fas	Gene	355
9857230	300	310	Fas ligand	Gene	356
9857230	404	415	Fas antigen	Gene	355
9857230	540	551	Fas antigen	Gene	355
9857230	748	758	Fas ligand	Gene	356
9857230	846	857	Fas antigen	Gene	355
9857230	1096	1106	Fas ligand	Gene	356
9857230	1223	1233	Fas ligand	Gene	356
9857230	1337	1348	Fas antigen	Gene	355
9857230	1430	1441	Fas antigen	Gene	355
9857230	1631	1634	Fas	Gene	355
9857230	1635	1645	Fas ligand	Gene	356
9857230	1708	1719	Fas antigen	Gene	355

11781689|t|Haplotype analysis in Icelandic and Finnish BRCA2 999del5 breast cancer families.
11781689|a|The 999del5 mutation is the single, strong BRCA2 founder mutation in Iceland and the most common BRCA1/2 founder mutation in Finland. To evaluate the origin and time since spreading of the 999del5 mutation in Iceland and in Finland, we constructed haplotypes with polymorphic markers within and flanking the BRCA2 gene in a set of 18 Icelandic and 10 Finnish 999del5 breast cancer families. All Icelandic families analysed shared a common core haplotype of about 1.7 cM. The common ancestors for the Icelandic families studied were estimated to trace back to 340-1000 years, not excluding the possibility that the mutation was brought to Iceland during the settlement of the country. Analysis of the Finnish families revealed two distinct haplotypes. A rare one, found in three families in the old settlement region in southwestern Finland, shared a four-marker (0.5 cM) core haplotype with the Icelandic 999del5 haplotype. A distinct approximately 6 cM haplotype was shared by seven 999del5 Finnish families estimated to have a common ancestry 140-300 years ago. These families cluster in two geographical regions in Finland, in the very same area as those with the rare haplotype and also in the most eastern, late settlement region of Finland. The results may indicate a common ancient origin for the 999del5 mutation in Iceland and in Finland, but distinct mutational events cannot be ruled out. The surprising finding of the same mutation in two completely different haplotypes in a sparsely populated area in Finland may suggest gene conversion.
11781689	44	49	BRCA2	Gene	675
11781689	125	130	BRCA2	Gene	675
11781689	179	184	BRCA1	Gene	672
11781689	179	186	BRCA1/2	Gene	675
11781689	390	395	BRCA2	Gene	675

11854171|t|KRIT1 association with the integrin-binding protein ICAP-1: a new direction in the elucidation of cerebral cavernous malformations (CCM1) pathogenesis.
11854171|a|Mutations in KRIT1, a protein initially identified based on a yeast two-hybrid interaction with the RAS-family GTPase RAP1A, are responsible for the development of the inherited vascular disorder cerebral cavernous malformations (CCM1). As the function of the KRIT1 protein and its role in CCM pathogenesis remain unknown, we performed yeast two-hybrid screens to identify additional protein binding partners. A fragment containing the N-terminal 272 amino acid residues of KRIT1, a region lacking similarity to any known protein upon database searches, was used as bait. From parallel screens of human fetal brain and HeLa cDNA libraries, we obtained multiple independent isolates of human integrin cytoplasmic domain-associated protein-1 (ICAP-1) as interacting clones. The interaction of KRIT1 and ICAP-1 was confirmed by GST-KRIT1 trapping of endogenous ICAP-1 from 293T cells. The alpha isoform of ICAP-1 is a 200 amino acid serine/threonine-rich phosphoprotein which binds the cytoplasmic tail of beta1 integrins. We show that mutagenesis of the N-terminal KRIT1 NPXY amino acid sequence, a motif critical for ICAP-1 binding to beta1 integrin molecules, completely abrogates the KRIT1/ICAP-1 interaction. The interaction between ICAP-1 and KRIT1, and the presence of a FERM domain in the latter, suggest that KRIT1 might be involved in the bidirectional signaling between integrin molecules and the cytoskeleton. Furthermore, these data suggest that KRIT1 might affect cell adhesion processes via integrin signaling in CCM1 pathogenesis.
11854171	0	5	KRIT1	Gene	889
11854171	52	58	ICAP-1	Gene	9270
11854171	165	170	KRIT1	Gene	889
11854171	270	275	RAP1A	Gene	5906
11854171	412	417	KRIT1	Gene	889
11854171	626	631	KRIT1	Gene	889
11854171	843	891	integrin cytoplasmic domain-associated protein-1	Gene	9270
11854171	893	899	ICAP-1	Gene	9270
11854171	943	948	KRIT1	Gene	889
11854171	953	959	ICAP-1	Gene	9270
11854171	977	980	GST	Gene	-1
11854171	981	986	KRIT1	Gene	889
11854171	1010	1016	ICAP-1	Gene	9270
11854171	1055	1061	ICAP-1	Gene	9270
11854171	1155	1170	beta1 integrins	Gene	3688
11854171	1215	1220	KRIT1	Gene	889
11854171	1268	1274	ICAP-1	Gene	9270
11854171	1286	1300	beta1 integrin	Gene	3688
11854171	1337	1342	KRIT1	Gene	889
11854171	1343	1349	ICAP-1	Gene	9270
11854171	1387	1393	ICAP-1	Gene	9270
11854171	1398	1403	KRIT1	Gene	889
11854171	1467	1472	KRIT1	Gene	889
11854171	1608	1613	KRIT1	Gene	889

11875050|t|Mutations in the inosine monophosphate dehydrogenase 1 gene (IMPDH1) cause the RP10 form of autosomal dominant retinitis pigmentosa.
11875050|a|Autosomal dominant retinitis pigmentosa (adRP) is a heterogeneous set of progressive retinopathies caused by several distinct genes. One locus, the RP10 form of adRP, maps to human chromosome 7q31.1 and may account for 5-10% of adRP cases among Americans and Europeans. We identified two American families with the RP10 form of adRP by linkage mapping and used these families to reduce the linkage interval to 3.45 Mb between the flanking markers D7S686 and RP-STR8. Sequence and transcript analysis identified 54 independent genes within this region, at least 10 of which are retinal-expressed and thus candidates for the RP10 gene. A screen of retinal transcripts comparing retinas from normal mice to retinas from crx-/crx- knockout mice (with poorly differentiated photoreceptors) demonstrated a 6-fold reduction in one candidate, inosine monophosphate dehydrogenase 1 (IMPDH1; EC 1.1.1.205). Since many of the genes known to cause retinitis pigmentosa are under CRX control in photoreceptors, IMPDH1 became a high-priority candidate for mutation screening. DNA sequencing of affected individuals from the two American RP10 families revealed a GAC-->AAC transition in codon 226 substituting an asparagine for an aspartic acid in both families. The identical mutation was also found in a British RP10 family. The Asp226Asn missense mutation is present in all affected individuals tested and absent from unaffected controls. The aspartic acid at codon 226 is conserved in all IMPDH genes, in all species examined, including bacteria, suggesting that this mutation is highly deleterious. Subsequent screening of probands from 60 other adRP families revealed an additional family with this mutation, confirming its association with retinitis pigmentosa and the relatively high frequency of this mutation. Another IMPDH1 substitution, Val268Ile, was also observed in this cohort of patients but not in controls. IMPDH1 is a ubiquitously expressed enzyme, functioning as a homotetramer, which catalyzed the rate-limiting step in de novo synthesis of guanine nucleotides. As such, it plays an important role in cyclic nucleoside metabolism within photoreceptors. Several classes of drugs are known to affect IMPDH isoenzymes, including nucleotide and NAD analogs, suggesting that small-molecule therapy may be available, one day, for RP10 patients.
11875050	17	54	inosine monophosphate dehydrogenase 1	Gene	3614
11875050	61	67	IMPDH1	Gene	3614
11875050	79	83	RP10	Gene	3614
11875050	281	285	RP10	Gene	3614
11875050	448	452	RP10	Gene	3614
11875050	756	760	RP10	Gene	3614
11875050	850	853	crx	Gene	1406
11875050	855	858	crx	Gene	1406
11875050	968	1005	inosine monophosphate dehydrogenase 1	Gene	3614
11875050	1007	1013	IMPDH1	Gene	3614
11875050	1100	1103	CRX	Gene	1406
11875050	1131	1137	IMPDH1	Gene	3614
11875050	1256	1260	RP10	Gene	3614
11875050	1432	1436	RP10	Gene	3614
11875050	1946	1952	IMPDH1	Gene	3614
11875050	2044	2050	IMPDH1	Gene	3614
11875050	2464	2468	RP10	Gene	3614

11909764|t|Lead induced DNA strand breaks in lymphocytes of exposed workers: role of reactive oxygen species and protein kinase C.
11909764|a|Lead and lead compounds play a significant role in modern industry; a wide variety of population is at risk of occupational exposure and lead is suspected to be a human carcinogen. The biochemical and molecular mechanisms of lead toxicity are poorly understood, but emerging data suggest that some of the effects of lead may be due to its interference with calcium in the activation of protein kinase C (PKC) and/or through production of reactive oxygen species (ROS). Many of these results are conducted in vitro on cell lines or ex vivo on human lymphocytes treated in vitro. We, therefore, performed a study on the induction of DNA damage, using the alkaline comet assay, in lymphocytes of battery plant workers. To elucidate in vivo the mechanism(s) responsible for this effect, we determined ROS production, and glutathione (GSH) levels in living cells using the fluorescent probe (2',7'-dichlorofluorescein and monochlorobimane, respectively). Subcellular fractions were obtained from sonicated lymphocytes; cytosolic and membrane expression of PKC isoforms (alpha, and zeta) was evaluated after electrophoresis by immunoblot analysis. The results indicate that lead-exposed workers have significantly elevated levels of DNA breaks compared to the unexposed group. A multivariate analysis of variance (ANOVA) shows that the most common confounding factors (smoking, drinking and age) have no synergistic effects with lead-exposure on the comet parameters or on GSH levels and ROS production. The logistic regression analysis distinguishing the exposed and non-exposed indicates that only GSH with tail moment are selected as significant risk factors. There is a significant positive correlation with ROS production and negative correlation with GSH levels. The content of PKC alpha in cytosol and membranes is decreased 40% (indicating a down-regulation of protein), whereas PKC zeta isoform is not modified in an evident manner. Our results suggest that lead-exposure induces an increase of DNA breakage with an alternate cellular redox state and a significant down-regulation of PKC alpha, suggesting that this metal may act as a tumor promoter.
11909764	102	118	protein kinase C	Gene	-1
11909764	506	522	protein kinase C	Gene	-1
11909764	524	527	PKC	Gene	-1
11909764	1171	1190	PKC isoforms (alpha	Gene	5578
11909764	1171	1201	PKC isoforms (alpha, and zeta)	Gene	5590
11909764	1898	1907	PKC alpha	Gene	5578
11909764	2001	2009	PKC zeta	Gene	5590
11909764	2207	2216	PKC alpha	Gene	5578

11966400|t|The pharmacogenetics of NAT: structural aspects.
11966400|a|Arylamine N-acetyltransferases (NATs) catalyze the transfer of an acetyl group from acetyl-CoA to arylhydrazines and to arylamine drugs and carcinogens or to their N-hydroxylated metabolites. NAT plays an important role in detoxification and metabolic activation of xenobiotics and was first identified as the enzyme responsible for inactivation of the antitubercular drug isoniazid, an arylhydrazine. The rate of inactivation was polymorphically distributed in the population: the first example of interindividual pharmacogenetic variation. Polymorphism in NAT activity is primarily due to single nucleotide polymorphisms (SNPs) in the coding region of NAT genes. NAT enzymes are widely distributed in eukaryotes and genome sequences have revealed many homologous members of this enzyme family in prokaryotes. The structures of S almonella typhimurium and Mycobacterium smegmatis NATs have been determined, revealing a unique fold in which a catalytic triad (Cys-His-Asp) forms the active site. Determination of prokaryotic and eukaryotic NAT structures could lead to a better understanding of their role in xenobiotics and endogenous metabolism.

11973627|t|Inherited and de novo mutations in sporadic cases of DYT1-dystonia.
11973627|a|A study of Danish probands with primary torsion dystonia is presented. The probands were examined clinically and biochemically to exclude secondary dystonia. Mutation analyses for the GAG-deletion in the DYT1 gene were performed on 107 probands; and the mutation was detected in three. All three probands had the classical phenotype of DYT1-dystonia, but only one had a family history of dystonia. The other two probands had, obviously, sporadic DYT1-dystonia, one of which was caused by a de novo mutation, while the other one had a parent being an asymptomatic carrier. De novo mutations in the DYT1 gene are seldom reported although independent founder mutations are known to have occurred. The frequency of DYT1-dystonia was low in our study even though several probands had early onset generalised dystonia. None of the probands in our study with other types of dystonia had the GAG-deletion as reported in other studies. The difficulties in genetic counselling concerning the heterogeneity of dystonia exemplified by DYT1-dystonia are outlined.
11973627	53	57	DYT1	Gene	1861
11973627	272	276	DYT1	Gene	1861
11973627	404	408	DYT1	Gene	1861
11973627	514	518	DYT1	Gene	1861
11973627	665	669	DYT1	Gene	1861
11973627	779	783	DYT1	Gene	1861
11973627	1091	1095	DYT1	Gene	1861

12007217|t|The IARC TP53 database: new online mutation analysis and recommendations to users.
12007217|a|Mutations in the tumor suppressor gene TP53 are frequent in most human cancers. Comparison of the mutation patterns in different cancers may reveal clues on the natural history of the disease. Over the past 10 years, several databases of TP53 mutations have been developed. The most extensive of these databases is maintained and developed at the International Agency for Research on Cancer. The database compiles all mutations (somatic and inherited), as well as polymorphisms, that have been reported in the published literature since 1989. The IARC TP53 mutation dataset is the largest dataset available on the variations of any human gene. The database is available at www.iarc.fr/P53/. In this paper, we describe recent developments of the database. These developments include restructuring of the database, which is now patient-centered, with more detailed annotations on the patient (carcinogen exposure, virus infection, genetic background). In addition, a new on-line application to retrieve somatic mutation data and analyze mutation patterns is now available. We also discuss limitations on the use of the database and provide recommendations to users.
12007217	9	13	TP53	Gene	7157
12007217	122	126	TP53	Gene	7157
12007217	321	325	TP53	Gene	7157
12007217	635	639	TP53	Gene	7157

12052141|t|Human flavin-containing monooxygenase (form 3): polymorphisms and variations in chemical metabolism.
12052141|a|The human flavin-containing monooxygenases catalyze the oxygenation of nucleophilic heteroatom-containing drugs, xenobiotics and endogenous materials. Evidence for six forms of the FMO gene exist but it is FMO form 3 (FMO3) that is the prominent form in adult human liver that is likely to be associated with the bulk of FMO-mediated metabolism. An understanding of the substrate specificity of human FMO3 is beginning to emerge and several examples of drugs and chemicals extensively metabolized by FMO3 have been reported. Expression of FMO3 is species- and tissue-specific, but unlike human cytochrome P450 (CYP450), mammalian FMO3 does not appear to be inducible. Interindividual variation in FMO3-dependent metabolism of drugs, chemicals and endogenous materials is therefore more likely to be due to genetic and not environmental effects. Certain mutations of the human FMO3 gene have been associated with abnormal N-oxygenation of trimethylamine. Deficient N-oxygenation of trimethylamine results in a condition called trimethylaminuria. Some treatment strategies for this inborn error of metabolism are discussed. Other common variants of the FMO3 gene including E158K, V257M and E308G have been observed. It is possible that allelic variation of human FMO3 causes abnormal metabolism of chemicals and has clinical implications for human drug metabolism, but this is an understudied area. Human FMO3 allelic variation may eventually be shown to contribute to interindividual and interethnic variability in FMO3-mediated metabolism. Human FMO3 may be another example of an environmental gene that participates in a protective mechanism to help shield humans from potentially toxic exposure to chemicals. Heterogeneity in the relative frequencies of single and multiple site alleles, haplotypes and genotypes of the human FMO3 amongst various ethnic groups suggests population differences.
12052141	6	46	flavin-containing monooxygenase (form 3)	Gene	2328
12052141	307	317	FMO form 3	Gene	2328
12052141	319	323	FMO3	Gene	2328
12052141	502	506	FMO3	Gene	2328
12052141	601	605	FMO3	Gene	2328
12052141	640	644	FMO3	Gene	2328
12052141	695	710	cytochrome P450	Gene	-1
12052141	731	735	FMO3	Gene	2328
12052141	798	802	FMO3	Gene	2328
12052141	977	981	FMO3	Gene	2328
12052141	1252	1256	FMO3	Gene	2328
12052141	1362	1366	FMO3	Gene	2328
12052141	1504	1508	FMO3	Gene	2328
12052141	1615	1619	FMO3	Gene	2328
12052141	1647	1651	FMO3	Gene	2328
12052141	1929	1933	FMO3	Gene	2328

12166659|t|Twenty single-nucleotide polymorphisms in four genes encoding cardiac ion channels.
12166659|a|We here report 20 novel single-nucleotide polymorphisms in four genes that are potentially involved in the excitement of cardiomyocytes: 1 in KCNA5 (encoding Kv1.5), 5 in KCNAB1 (encoding Kvbeta1.3), 5 in KCNIP2 (encoding KChIP2), and 9 in CACNA1C (encoding a cardiac L-type voltage-dependent calcium ion channel, dihydropyridine receptor). We also examined their allelic frequencies in Japanese individuals. These data will be useful for genetic association studies designed to investigate secondary long QT syndrome or other circulatory disorders.
12166659	226	231	KCNA5	Gene	3741
12166659	242	247	Kv1.5	Gene	3741
12166659	255	261	KCNAB1	Gene	7881
12166659	272	281	Kvbeta1.3	Gene	7881
12166659	289	295	KCNIP2	Gene	30819
12166659	306	312	KChIP2	Gene	30819
12166659	324	331	CACNA1C	Gene	775

12205109|t|Vitreoretinopathy with phalangeal epiphyseal dysplasia, a type II collagenopathy resulting from a novel mutation in the C-propeptide region of the molecule.
12205109|a|A large family with dominantly inherited rhegmatogenous retinal detachment, premature arthropathy, and development of phalangeal epiphyseal dysplasia, resulting in brachydactyly was linked to COL2A1, the gene encoding proalpha1(II) collagen. Mutational analysis of the gene by exon sequencing identified a novel mutation in the C-propeptide region of the molecule. The glycine to aspartic acid change occurred in a region that is highly conserved in all fibrillar collagen molecules. The resulting phenotype does not fit easily into pre-existing subgroups of the type II collagenopathies, which includes spondyloepiphyseal dysplasia, and the Kniest, Strudwick, and Stickler dysplasias.
12205109	349	355	COL2A1	Gene	1280
12205109	375	397	proalpha1(II) collagen	Gene	1280

12215838|t|Haplotype study of West European and North African Unverricht-Lundborg chromosomes: evidence for a few founder mutations.
12215838|a|Unverricht-Lundborg disease (ULD) is a progressive myoclonus epilepsy common in Finland and North Africa, and less common in Western Europe. ULD is mostly caused by expansion of a dodecamer repeat in the cystatin B gene ( CSTB) promoter. We performed a haplotype study of ULD chromosomes (ULDc) with the repeat expansion. We included 48 West European Caucasian (WEC) and 47 North African (NA) ULDc. We analysed eight markers flanking CSTB(GT10-D21S1890-D21S1885-D21S2040-D21S1259- CSTB-D21S1912-PFKL-D21S171) and one intragenic variant in the CSTB 3' UTR (A2575G). We observed a founder effect in most of the NA ULD patients, as 61.7% of the NA ULDc (29/47) shared the same haplotype, A1 (1-1-A-1-6-7), for markers D21S1885-D21S2040-A2575G-D21S1259-D21S1912-PFKL. Moreover, if we considered only the markers D21S1885, D21S2040, A2575G and D21S1259, 43 of the 47 NA ULDc shared the same alleles 1-1-A-1, haplotype A. As previously shown, the WEC ULDc were heterogeneous. However, the Baltic haplotype, A3 (5-1-1-A-1-1), was observed in ten WEC ULDc (20.8%) and the CSTB 3'UTR variant, which we called the Alps variant, was observed in 17 ULDc (35.4%). Finally, as almost all NA patients, like Scandinavian patients, were of the haplotype A, we assumed that there was an ancient common founder effect in NA and Baltic ULD patients. We estimated that the putative most recent common ancestral ULD carrier with this haplotype A must have existed about 2,500 years ago (100-150 generations). Finally, this work provides evidence for the existence of only a small number of founder mutations in ULD.
12215838	326	336	cystatin B	Gene	1476
12215838	344	348	CSTB	Gene	1476
12215838	556	560	CSTB	Gene	1476
12215838	603	607	CSTB	Gene	1476
12215838	617	621	PFKL	Gene	5211
12215838	665	669	CSTB	Gene	1476
12215838	880	884	PFKL	Gene	5211
12215838	1186	1190	CSTB	Gene	1476

12220456|t|Three novel mutations of the PKD1 gene in Korean patients with autosomal dominant polycystic kidney disease.
12220456|a|Mutations at the PKD1 locus account for 85% of cases of the common genetic disorder called autosomal dominant polycystic kidney disease (ADPKD). Screening for mutations of the PKD1 gene is complicated by the genomic structure of the 5'-duplicated region encoding 75% of the gene. To date, more than 90 mutations of the PKD1 gene have been reported in the European and American populations, and relatively little information is available concerning the pattern of mutations present in the Asian populations. We looked for mutations of the PKD1 gene in 51 unrelated Korean ADPKD patients, using polymerase chain reaction (PCR) with primer pairs located in the 3' single-copy region of the PKD1 gene and by single-strand conformation polymorphism (SSCP) analysis. We found three novel mutations, a G to A substitution at nucleotide 11012 (G3601S), a C to A substitution at nucleotide 11312 (Q3701X), and a C to T substitution at nucleotide 12971 (P4254S), and a single polymorphism involving a G to C substitution at nucleotide 11470 (L3753L). These mutations were not found in control individuals, and no other mutations in the 3' single-copy region of the PKD1 gene of patients with these mutations were observed. In particular, P4254S segregated with the disease phenotype. The clinical data of affected individuals from this study, and of previously reported Korean PKD1 mutations, showed that patients with frameshift or nonsense mutations were more prone to develop end-stage renal failure than those with missense mutations. Our findings indicate that many different PKD1 mutations are likely to be responsible for ADPKD in the Korean population, as in the Western population.
12220456	29	33	PKD1	Gene	5310
12220456	126	130	PKD1	Gene	5310
12220456	285	289	PKD1	Gene	5310
12220456	428	432	PKD1	Gene	5310
12220456	647	651	PKD1	Gene	5310
12220456	796	800	PKD1	Gene	5310
12220456	1264	1268	PKD1	Gene	5310
12220456	1476	1480	PKD1	Gene	5310
12220456	1680	1684	PKD1	Gene	5310

12384774|t|Evidence for a founder effect for pseudoxanthoma elasticum in the Afrikaner population of South Africa.
12384774|a|Pseudoxanthoma elasticum (PXE) is a heritable elastic tissue disorder recently shown to be attributable to mutations in the ABCC6 ( MRP6) gene. Whereas PXE has been identified in all ethnic groups studied to date, the prevalence of this disease in various populations is uncertain, although often assumed to be similar. A notable exception however is the prevalence of PXE among South African Afrikaners. A previous report has suggested that a founder effect may explain the higher prevalence of PXE in Afrikaners, a European-derived population that first settled in South Africa in the 17th century. To investigate this hypothesis, we performed haplotype and mutational analysis of DNA from 24 South African families of Afrikaner, British and Indian descent. Among the 17 Afrikaner families studied, three common haplotypes and six different disease-causing variants were identified. Three of these mutant alleles were missense variants, two were nonsense mutations and one was a single base-pair insertion. The most common variant accounted for 53% of the PXE alleles, whereas other mutant alleles appeared at lower frequencies ranging from 3% to 12%. Haplotype analysis of the Afrikaner families showed that the three most frequent mutations were identical-by-descent, indicating a founder origin of PXE in this population.
12384774	228	233	ABCC6	Gene	368
12384774	236	240	MRP6	Gene	368

12442272|t|D90A-SOD1 mediated amyotrophic lateral sclerosis: a single founder for all cases with evidence for a Cis-acting disease modifier in the recessive haplotype.
12442272|a|More than 100 different heterozygous mutations in copper/zinc superoxide dismutase (SOD1) have been found in patients with amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. Uniquely, D90A-SOD1 has been identified in recessive, dominant and apparently sporadic pedigrees. The phenotype of homozygotes is stereotyped with an extended survival, whereas that of affected heterozygotes varies. The frequency of D90A-SOD1 is 50 times higher in Scandinavia (2.5%) than elsewhere, though ALS prevalence is not raised there. Our earlier study indicated separate founders for recessive and dominant/sporadic ALS and we proposed a disease-modifying factor linked to the recessive mutation. Here we have doubled our sample set and employed novel markers to characterise the mutation's origin and localise any modifying factor. Linkage disequilibrium analysis indicates that D90A homozygotes and heterozygotes share a rare haplotype and are all descended from a single ancient founder (alpha 0.974) c.895 generations ago. Homozygotes arose subsequently only c.63 generations ago (alpha 0.878). Recombination has reduced the region shared by recessive kindreds to 97-265 kb around SOD1, excluding all neighbouring genes. We propose that a cis-acting regulatory polymorphism has arisen close to D90A-SOD1 in the recessive founder, which decreases ALS susceptibility in heterozygotes and slows disease progression.
12442272	5	9	SOD1	Gene	6647
12442272	241	245	SOD1	Gene	6647
12442272	367	371	SOD1	Gene	6647
12442272	590	594	SOD1	Gene	6647
12442272	1346	1350	SOD1	Gene	6647
12442272	1464	1468	SOD1	Gene	6647

12471205|t|SNP S1103Y in the cardiac sodium channel gene SCN5A is associated with cardiac arrhythmias and sudden death in a white family.
12471205|a|Cardiac arrhythmias cause 400 000 sudden deaths annually in the United States alone. Mutations in the cardiac sodium channel gene SCN5A on chromosome 3p21 cause cardiac arrhythmias and sudden death. In this study, we define an SCN5A mutation, S1103Y, in a white family associated with syncope, ventricular fibrillation, and sudden death. A very recent study reported the same mutation in 13.2% of African Americans, but not in the white population. Our study shows that mutation S1103Y does exist in the white population, and it is associated with a considerable risk of syncope, ventricular arrhythmia, ventricular fibrillation, and sudden death in this population.
12471205	46	51	SCN5A	Gene	6331
12471205	257	262	SCN5A	Gene	6331
12471205	354	359	SCN5A	Gene	6331

12471593|t|Common sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk.
12471593|a|Rare germline mutations of macrophage scavenger receptor 1 (MSR1) gene were reported to be associated with prostate cancer risk in families with hereditary prostate cancer (HPC) and in patients with non-HPC (Xu et al. 2002). To further evaluate the role of MSR1 in prostate cancer susceptibility, at Johns Hopkins Hospital, we studied five common variants of MSR1 in 301 patients with non-HPC who underwent prostate cancer treatment and in 250 control subjects who participated in prostate cancer-screening programs and had normal digital rectal examination and PSA levels (<4 ng/ml). Significantly different allele frequencies between case subjects and control subjects were observed for each of the five variants (P value range.01-.04). Haplotype analyses provided consistent findings, with a significant difference in the haplotype frequencies from a global score test (P=.01). Because the haplotype that is associated with the increased risk for prostate cancer did not harbor any of the known rare mutations, it appears that the observed association of common variants and prostate cancer risk are independent of the effect of the known rare mutations. These results consistently suggest that MSR1 may play an important role in prostate carcinogenesis.
12471593	32	63	macrophage scavenger receptor 1	Gene	4481
12471593	138	169	macrophage scavenger receptor 1	Gene	4481
12471593	171	175	MSR1	Gene	4481
12471593	368	372	MSR1	Gene	4481
12471593	470	474	MSR1	Gene	4481
12471593	673	676	PSA	Gene	354
12471593	1309	1313	MSR1	Gene	4481

12749065|t|Subcortical band heterotopia with simplified gyral pattern and syndactyly.
12749065|a|We describe a girl with an unusual form of subcortical band heterotopia (SBH) and a complex malformation syndrome. SBH had an irregular inner margin, organized in contiguous fascicles of migrating neurons, sometimes giving the appearance of many small contiguous gyri. The true cortex had decreased thickness and showed a simplified gyral pattern with decreased number of gyri, which were usually of increased width, and shallow sulci. The cerebellum was hypoplastic. Additional features included epicanthal folds, hypertelorism, small nose with hypoplastic nares, bilateral syndactyly of the toes, pulmonary valve stenosis, atrial and ventricular septal defects. At the age of 1 year the patient had severe developmental delay and epilepsy. Chromosome studies and mutation analysis of the DCX and LIS1 genes gave negative results. This observation delineates a new multiple congenital abnormalities mental retardation syndrome and confirms genetic heterogeneity of SBH.
12749065	865	868	DCX	Gene	1641
12749065	873	877	LIS1	Gene	5048

13679998|t|Lack of association between the G protein beta3 subunit gene and essential hypertension in Chinese: a case-control and a family-based study.
13679998|a|A C825T polymorphism of the gene encoding the G protein beta3 subunit (GNB3) is associated with enhanced G protein activity and increased intracellular signal transduction. The 825T allele has been implicated in the development of hypertension in some ethnic groups, especially in whites. Studies in Asians and blacks are more controversial, and little information is available on this polymorphism in the susceptibility to hypertension in the Chinese population. Furthermore, the inconsistency between studies may be due to genetic heterogeneity of the population selected and/or the lack of statistical power. We investigated the relationship of this polymorphism with hypertension in two independent northern Chinese populations using both a case-control and a family-based study design. The GNB3 C825T polymorphism was determined by polymerase chain reaction and restriction enzyme digestion. In the case-control study which included 585 hypertensive case subjects and 580 normotensive control subjects there was no significant association between the polymorphism and hypertension status or blood pressure levels. The lack of association was confirmed by the results obtained in 181 hypertensive families using both transmission disequilibrium test and sib transmission disequilibrium test. No preferential transmission was observed for the GNB3 825T allele to the affected subjects. Furthermore, there was no significant association between the polymorphism and body mass index in the case-control study. Therefore our work does not provide evidence in favor of GNB3 C825T being a candidate gene for conferring genetic susceptibility to hypertension or obesity in northern Chinese population.
13679998	32	55	G protein beta3 subunit	Gene	2784
13679998	187	210	G protein beta3 subunit	Gene	2784
13679998	212	216	GNB3	Gene	2784
13679998	936	940	GNB3	Gene	2784
13679998	1487	1491	GNB3	Gene	2784
13679998	1709	1713	GNB3	Gene	2784

14508509|t|Gene-gene interaction between the monoamine oxidase A gene and solute carrier family 6 (neurotransmitter transporter, noradrenalin) member 2 gene in anorexia nervosa (restrictive subtype).
14508509|a|We earlier found an association between anorexia nervosa (AN) restrictive subtype (AN-R) and an inserted sequence within the NETpPR, a polymorphic region located in the promoter of the solute carrier family 6 (neurotransmitter transporter, noradrenalin) member 2 (SLC6A2) gene. To further examine the noradrenergic system in AN-R we performed an association study with a functional polymorphism (MAOA-uVNTR) in the promoter of the monoamine oxidase A (MAOA) gene. Since monoamine oxidase A metabolises noradrenalin, a positive association with the MAOA gene would be biologically plausible. The transmission disequilibrium test and 95 trios/duos (AN-R females+biological parents) showed the main effect of the longer, more transcriptionally active form of the MAOA-uVNTR (MAOA-L) to be statistically non-significant (McNemar's chi(2)=1.4, df=1, P=0.238, odds ratio: 1.4, 95% CI 0.8-2.7). A case-control approach supported this finding. We then stratified the MAOA-uVNTR TDT data according to the (a) NETpPR genotype of the AN-R females, and (b) NETpPR allele transmitted from NETpPR-S4/L4 heterozygous mothers. In both cases, contingency table analysis revealed previously unreported gene-gene interaction between the MAOA and SLC6A2 genes (P=0.019 and 0.019, respectively). Receiving an MAOA-L allele more than doubles the risk for developing AN-R, conditional on an individual also being a NETpPR-L4 homozygote (stratum-specific odds ratio: 2.4, 95% CI 1.1-6.0). These results suggest important involvement of the noradrenergic system in the biological underpinnings of AN-R.
14508509	34	53	monoamine oxidase A	Gene	4128
14508509	63	140	solute carrier family 6 (neurotransmitter transporter, noradrenalin) member 2	Gene	6530
14508509	374	451	solute carrier family 6 (neurotransmitter transporter, noradrenalin) member 2	Gene	6530
14508509	453	459	SLC6A2	Gene	6530
14508509	585	589	MAOA	Gene	4128
14508509	620	639	monoamine oxidase A	Gene	4128
14508509	641	645	MAOA	Gene	4128
14508509	659	678	monoamine oxidase A	Gene	4128
14508509	737	741	MAOA	Gene	4128
14508509	949	953	MAOA	Gene	4128
14508509	961	965	MAOA	Gene	4128
14508509	1148	1152	MAOA	Gene	4128
14508509	1159	1162	TDT	Gene	1791
14508509	1407	1411	MAOA	Gene	4128
14508509	1416	1422	SLC6A2	Gene	6530
14508509	1477	1481	MAOA	Gene	4128

14571269|t|Evidence for a QTL on chromosome 19 influencing LDL cholesterol levels in the general population.
14571269|a|The genetic basis of cardiovascular disease (CVD) with its complex etiology is still largely elusive. Plasma levels of lipids and apolipoproteins are among the major quantitative risk factors for CVD and are well-established intermediate traits that may be more accessible to genetic dissection than clinical CVD end points. Chromosome 19 harbors multiple genes that have been suggested to play a role in lipid metabolism and previous studies indicated the presence of a quantitative trait locus (QTL) for cholesterol levels in genetic isolates. To establish the relevance of genetic variation at chromosome 19 for plasma levels of lipids and apolipoproteins in the general, out-bred Caucasian population, we performed a linkage study in four independent samples, including adolescent Dutch twins and adult Dutch, Swedish and Australian twins totaling 493 dizygotic twin pairs. The average spacing of short-tandem-repeat markers was 6-8 cM. In the three adult twin samples, we found consistent evidence for linkage of chromosome 19 with LDL cholesterol levels (maximum LOD scores of 4.5, 1.7 and 2.1 in the Dutch, Swedish and Australian sample, respectively); no indication for linkage was observed in the adolescent Dutch twin sample. The QTL effects in the three adult samples were not significantly different and a simultaneous analysis of the samples increased the maximum LOD score to 5.7 at 60 cM pter. Bivariate analyses indicated that the putative LDL-C QTL also contributed to the variance in ApoB levels, consistent with the high genetic correlation between these phenotypes. Our study provides strong evidence for the presence of a QTL on chromosome 19 with a major effect on LDL-C plasma levels in outbred Caucasian populations.
14571269	1600	1604	ApoB	Gene	338

14610350|t|A 3.4-kbp transcript of ZNF331 is solely expressed in follicular thyroid adenomas.
14610350|a|Translocations involving chromosomal region 19q13 are a frequent finding in follicular adenomas of the thyroid and might represent the most frequent type of structural aberration in human epithelial tumors. By positional cloning, a putative candidate gene, ZNF331 (formerly RITA) located close to the breakpoint was identified. Recently, aberrant expression of ZNF331 has been described in two cell lines of follicular thyroid adenomas with aberrations in 19q13 indicating an involvement of ZNF331 in tumorigenesis. Nevertheless, knowledge about structure and expression of ZNF331 is limited. We performed RACE-PCR and genomic sequence analyses to gain a deeper insight into its molecular structure. To elucidate ZNF331 expression patterns we performed Northern blot analyses on various normal tissues as well as on thyroid carcinoma and adenoma cell lines. Herein, unique expression of a 3.4-kbp transcript is described in thyroid adenoma cell lines with 19q13 aberrations, which was not detected either in normal tissues or in thyroid carcinoma cell lines.
14610350	24	30	ZNF331	Gene	55422
14610350	340	346	ZNF331	Gene	55422
14610350	357	361	RITA	Gene	55422
14610350	444	450	ZNF331	Gene	55422
14610350	574	580	ZNF331	Gene	55422
14610350	657	663	ZNF331	Gene	55422
14610350	796	802	ZNF331	Gene	55422

14613971|t|Developmentally-programmed FMRP expression in oligodendrocytes: a potential role of FMRP in regulating translation in oligodendroglia progenitors.
14613971|a|The fragile X mental retardation protein (FMRP) is a selective RNA-binding protein whose function is implicated in regulating protein synthesis of its mRNA targets. The lack of FMRP leads to abnormal synapse development in the brain and impaired learning/memory. Although FMRP is predominantly expressed in neurons of the adult brain, whether FMRP also functions in glia during early development remains elusive, since expression of FMRP in glia has not been rigorously examined. This is an important question because recent studies revealed important roles of glia in synaptic development. Here we report that in addition to the observed neuronal expression, FMRP expression is detected in oligodendroglia progenitor cells (OPCs), immature oligodendrocytes and oligodendroglia cell lines, where it interacts with a subgroup of oligodendrocyte-specific mRNAs, including the myelin basic protein (MBP) mRNA. FMRP expression gradually declines as oligodendrocytes differentiate in vitro and in the developing brain. The decline of FMRP expression during oligodendrocyte differentiation is associated with a vigorous up-regulation of the MBP protein. In addition, we show that the MBP 3'untranslated region (3'UTR) is necessary and sufficient for binding FMRP, and mediates translation inhibition of a reporter gene by FMRP specifically in oligodendrocytes. These results support the hypothesis that FMRP may participate in regulating translation of its bound mRNAs in oligodendroglia during early brain development.
14613971	27	31	FMRP	Gene	57532
14613971	84	88	FMRP	Gene	57532
14613971	151	187	fragile X mental retardation protein	Gene	57532
14613971	189	193	FMRP	Gene	57532
14613971	324	328	FMRP	Gene	57532
14613971	419	423	FMRP	Gene	57532
14613971	490	494	FMRP	Gene	57532
14613971	580	584	FMRP	Gene	57532
14613971	807	811	FMRP	Gene	57532
14613971	1021	1041	myelin basic protein	Gene	4155
14613971	1043	1046	MBP	Gene	4155
14613971	1054	1058	FMRP	Gene	57532
14613971	1176	1180	FMRP	Gene	57532
14613971	1282	1285	MBP	Gene	4155
14613971	1325	1328	MBP	Gene	4155
14613971	1399	1403	FMRP	Gene	57532
14613971	1463	1467	FMRP	Gene	57532
14613971	1544	1548	FMRP	Gene	57532

14644354|t|Propofol anesthesia in children does not induce sister chromatid exchanges in lymphocytes.
14644354|a|BACKGROUND: Propofol is frequently used for general anesthesia in children although little is known about possible genotoxic effects in humans. We investigated the formation of sister chromatid exchanges (SCE) in metaphase chromosomes of T-lymphocytes of children as a marker for possible genotoxocity following total intravenous anesthesia with propofol for minor surgical procedures. METHODS: 40 children ASA classification I-III were included (ASA I n=34, ASA II n=5, ASA III n=1) in the study. Anesthesia was induced by propofol (3mg/kg) and alfentanil. Succinylcholine or rocuronium were administered for muscle relaxation. After tracheal intubation anesthesia was maintained by continuous propofol infusion at 12 mg/(kgh). Blood samples were drawn before induction and after termination of anesthesia. Following a 72 h cell culture period, 25 T-lymphocyte metaphases per blood sample for all children were analyzed for SCE frequencies. RESULTS: Total intravenous anesthesia with propofol on children did not influence SCE rates in metaphase chromosomes of T-lymphocytes. No SCE differences could be detected between blood samples before initiation and after termination of anesthesia (Wilcoxon signed rank test). Slightly elevated SCE rates were obtained in T-lymphocytes of girls compared to boys, but these differences did not reach statistical significance. CONCLUSIONS: Propofol anesthesia under the chosen conditions did not induce the formation of SCE in children in vivo. No genotoxic effect of a short term exposure to propofol during pediatric anesthesia had been observed.

14722915|t|Y-chromosomal microsatellite mutation rates: differences in mutation rate between and within loci.
14722915|a|Precise estimates of mutation rates at Y-chromosomal microsatellite STR (short tandem repeat) loci make an important basis for paternity diagnostics and dating of Y chromosome lineage origins. There are indications of considerable locus mutation rate variability between (inter-) and within (intra-) loci. We have studied nine Y-STR loci-DYS19, DYS389I/II, DYS390, DYS391, DYS392, DYS393, DYS385, and DYS388-in 1,766 father-son pairs of confirmed paternity (a total of 15,894 meioses). Five biallelic markers were also analyzed in the fathers-Tat, YAP, 12f2, SRY1532, and 92R7-defining haplogroups 1, 2, 3, 4, 9, and 16, respectively. A total of 36 fragment length mutations were observed: 24 gains (22 single-step, two double-step) and 12 single-step losses. Thus, there was a significant surplus of gains (p=0.045). Overall, the mutation rate was positively correlated to STR repeat length and there was a significant relative excess of losses in long alleles and gains in short alleles (p=0.043). In contrast to the situation in autosomal STR loci and in MSY-1, no noteworthy correlation between mutation rate and the father's age at the child's birth was observed. We observed significant interlocus differences in Y-STR mutation rates (p<0.01). The number of observed mutations ranged from zero in DYS392 to eight in DYS391 and DYS390. We have also demonstrated obvious differences in mutation rates between the haplogroups studied (p=0.024), a phenomenon that is a reflection of the dependence of mutation rate on allele size. Our study has thus demonstrated the necessity of not only locus-specific, but even allele-specific, mutation rate estimates for forensic and population genetic purposes, and provides a considerable basis for such estimates.

14722929|t|Low frequency of deafness-associated GJB2 variants in Kenya and Sudan and novel GJB2 variants.
14722929|a|A large proportion of non-syndromic autosomal recessive deafness (NSARD) in many populations is caused by variants of the GJB2 gene. Here, the frequency of GJB2 variants was studied in 406 and 183 apparently unrelated children from Kenya and Sudan, respectively, with mostly severe to profound non-syndromic deafness. Nine (2.2 %) Kenyan and 12 (6.6 %) of the Sudanese children only were carriers of variants within the coding sequence of the GJB2 gene. Variants in the 5'-adjacent region were detected in further 115 individuals. A total of 10 novel variants was recognized, among them four variants in the adjacent 5'-region of the GJB2 coding exon 2 (g.3318-6T>A, g.3318-15C>T, g.3318-34C>T, g.3318-35T>G), a 6 base-pair deletion (g.3455_3460del [p.Asp46_Gln48delinsGlu]), a variant leading to a stop codon (g.3512C>A [p.Tyr65X]), synonymous variants (g.3395C>T [p.Thr26], g.3503C>T [p.Asn62], g.3627A>C [p.Arg104]), and one non-synonymous variant (g.3816C>A [p.Val167Met]). In addition, the previously described variants g.3352delG (commonly designated 30delG or 35 delG), g.3426G>A [p.Val37Ile], g.3697G>A [p.Arg127His], g.3774G>A [p.Val153Ile], and g.3795G>A [p.Gly160Ser] were identified. With the exception of g.3318-34C>T and g.3352delG, all variants occurred heterozygously. For most of the variants identified in the Kenyan and Sudanese study population, a causative association with NSARD appears to be unlikely. Compared to many other ethnic groups, deafness-associated variants of the coding region of GJB2 are rare in Sudan and Kenya, suggesting a role of other genetic, or epigenetic factors as a cause for deafness in these countries.
14722929	37	41	GJB2	Gene	2706
14722929	80	84	GJB2	Gene	2706
14722929	217	221	GJB2	Gene	2706
14722929	251	255	GJB2	Gene	2706
14722929	538	542	GJB2	Gene	2706
14722929	729	733	GJB2	Gene	2706
14722929	1611	1615	GJB2	Gene	2706

14755448|t|Clinical features of psychotic disorders and polymorphisms in HT2A, DRD2, DRD4, SLC6A3 (DAT1), and BDNF: a family based association study.
14755448|a|Schizophrenia is clinically heterogeneous and multidimensional, but it is not known whether this is due to etiological heterogeneity. Previous studies have not consistently reported association between any specific polymorphisms and clinical features of schizophrenia, and have primarily used case-control designs. We tested for the presence of association between clinical features and polymorphisms in the genes for the serotonin 2A receptor (HT2A), dopamine receptor types 2 and 4, dopamine transporter (SLC6A3), and brain-derived neurotrophic factor (BDNF). Two hundred seventy pedigrees were ascertained on the basis of having two or more members with schizophrenia or poor outcome schizoaffective disorder. Diagnoses were made using a structured interview based on the SCID. All patients were rated on the major symptoms of schizophrenia scale (MSSS), integrating clinical and course features throughout the course of illness. Factor analysis revealed positive, negative, and affective symptom factors. The program QTDT was used to implement a family-based test of association for quantitative traits, controlling for age and sex. We found suggestive evidence of association between the His452Tyr polymorphism in HT2A and affective symptoms (P = 0.02), the 172-bp allele of BDNF and negative symptoms (P = 0.04), and the 480-bp allele in SLC6A3 (= DAT1) and negative symptoms (P = 0.04). As total of 19 alleles were tested, we cannot rule out false positives. However, given prior evidence of involvement of the proteins encoded by these genes in psychopathology, our results suggest that more attention should be focused on the impact of these alleles on clinical features of schizophrenia.
14755448	62	66	HT2A	Gene	3356
14755448	68	72	DRD2	Gene	1813
14755448	74	78	DRD4	Gene	1815
14755448	80	86	SLC6A3	Gene	6531
14755448	88	92	DAT1	Gene	6531
14755448	99	103	BDNF	Gene	627
14755448	561	582	serotonin 2A receptor	Gene	3356
14755448	584	588	HT2A	Gene	3356
14755448	591	616	dopamine receptor types 2	Gene	1813
14755448	591	622	dopamine receptor types 2 and 4	Gene	1815
14755448	624	644	dopamine transporter	Gene	6531
14755448	646	652	SLC6A3	Gene	6531
14755448	659	692	brain-derived neurotrophic factor	Gene	627
14755448	694	698	BDNF	Gene	627
14755448	1358	1362	HT2A	Gene	3356
14755448	1419	1423	BDNF	Gene	627
14755448	1483	1489	SLC6A3	Gene	6531
14755448	1493	1497	DAT1	Gene	6531

14976162|t|Genomic evidence for recent positive selection at the human MDR1 gene locus.
14976162|a|The MDR1 multidrug transporter regulates the traffic of drugs, peptides and xenobiotics into the body as well as sensitive tissues like the brain, germ cells and the developing fetus. Hence, it may influence an individual's response to drugs as well as his/her susceptibility to complex diseases in which environmental factors, especially xenobiotics, play a role. Polymorphisms within this gene, especially single-nucleotide polymorphism e26/3435(C/T), have been variously associated with differences in MDR1 expression, function, drug response and disease susceptibility. Here, we report the detailed characterization of the haplotype and linkage disequilibrium architecture of the entire 200 kb of the MDR1 gene in five world populations, namely, Chinese, Malays, Indians, Caucasians and African-Americans. We observed varied haplotype diversity across the entire gene in the different populations. The major haplotype mh5, which contains the subhaplotype e12/1236T-e21/2677T-e26/3435T, is highly represented among the four non-African populations, while mh7, which contains the subhaplotype e12/1236C-e21/2677G-e26/3435C, accounts for over a third of African-American chromosomes. These observations are inconsistent with a simple population evolution model, but instead are suggestive of recent historical events that have maintained such long range linkage disequilibrium. Using a modified long-range haplotype test, we found statistically significant evidence of recent positive selection for the e21/2677T and e26/3435T alleles in the Chinese population, and for the e26/3435T allele in the Malay population. Interestingly, we also detected evidence for positive selection of the alternative allele e26/3435C in the African-American population. These data suggest that independent mutational events may have occurred on the mh5 and mh7 haplotypes of the MDR1 gene to confer positive selection in the non-African and African-American populations, respectively.
14976162	60	64	MDR1	Gene	5243
14976162	81	85	MDR1	Gene	5243
14976162	582	586	MDR1	Gene	5243
14976162	782	786	MDR1	Gene	5243
14976162	1939	1943	MDR1	Gene	5243
14976162	1939	1943	MDR1	Gene	23158

15099351|t|Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia.
15099351|a|Proprotein convertase subtilisin/kexin type 9 (PCSK9) is at a locus for autosomal dominant hypercholesterolemia, and recent data indicate that the PCSK9 gene is involved in cholesterol biosynthesis. Mutations within this gene have previously been found to segregate with hypercholesterolemia. In this study, DNA sequencing of the 12 exons of the PCSK9 gene has been performed in 51 Norwegian subjects with a clinical diagnosis of familial hypercholesterolemia where mutations in the low-density lipoprotein receptor gene and mutation R3500Q in the apolipoprotein B-100 gene had been excluded. Two novel missense mutations were detected in the catalytic subdomain of the PCSK9 gene. Two patients were heterozygotes for D374Y, and one patient was a double heterozygote for D374Y and N157K. D374Y segregated with hypercholesterolemia in the two former families where family members were available for study. Our findings support the notion that mutations in the PCSK9 gene cause autosomal dominant hypercholesterolemia.
15099351	17	22	PCSK9	Gene	255738
15099351	96	141	Proprotein convertase subtilisin/kexin type 9	Gene	255738
15099351	143	148	PCSK9	Gene	255738
15099351	243	248	PCSK9	Gene	255738
15099351	442	447	PCSK9	Gene	255738
15099351	579	611	low-density lipoprotein receptor	Gene	3949
15099351	644	664	apolipoprotein B-100	Gene	338
15099351	766	771	PCSK9	Gene	255738
15099351	1055	1060	PCSK9	Gene	255738

15106122|t|Disruption of contactin 4 (CNTN4) results in developmental delay and other features of 3p deletion syndrome.
15106122|a|3p deletion syndrome is a rare contiguous-gene disorder involving the loss of the telomeric portion of the short arm of chromosome 3 and characterized by developmental delay, growth retardation, and dysmorphic features. All reported cases have involved, at a minimum, the deletion of chromosome 3 telomeric to the band 3p25.3. Despite the presence of several genes in this region that are involved in neural development, a causative relationship between a particular transcript and the observed clinical manifestations has remained elusive. We have identified a child with characteristic physical features of 3p deletion syndrome and both verbal and nonverbal developmental delay who carries a de novo balanced translocation involving chromosomes 3 and 10. Fine mapping of this rearrangement demonstrates that the translocation breakpoint on chromosome 3 falls within the recently identified minimal candidate region for 3p deletion syndrome and disrupts the Contactin 4 (CNTN4) mRNA transcript at 3p26.2-3p26.3. This transcript (also known as BIG-2) is a member of the immunoglobulin super family of neuronal cell adhesion molecules involved in axon growth, guidance, and fasciculation in the central nervous system (CNS). Our results demonstrate the association of CNTN4 disruption with the 3p deletion syndrome phenotype and strongly suggest a causal relationship. These findings point to an important role for CNTN4 in normal and abnormal CNS development.
15106122	14	25	contactin 4	Gene	152330
15106122	27	32	CNTN4	Gene	152330
15106122	1068	1079	Contactin 4	Gene	152330
15106122	1081	1086	CNTN4	Gene	152330
15106122	1153	1158	BIG-2	Gene	152330
15106122	1376	1381	CNTN4	Gene	152330
15106122	1523	1528	CNTN4	Gene	152330

15116316|t|Offspring gender ratio and the rate of recurrent spontaneous miscarriages in jewish women at high risk for breast/ovarian cancer.
15116316|a|BRCA1/BRCA2 germline mutations are associated with an increased breast/ovarian cancer risk. Offspring gender ratios may be skewed against male births in BRCA1 mutation carriers. In addition, the lack of viable homozygous BRCA1/BRCA2-mutation carriers implies that recurrent miscarriages may be associated with homozygous fetuses. Jewish Israeli high-risk women who were tested for being carriers of the predominant BRCA1/BRCA2 mutations in Jewish high-risk families were analyzed for the sex of offspring and the rate of spontaneous miscarriages. Overall, 817 women participated: 393 BRCA1/BRCA2-mutation carriers (229 with breast/ovarian cancer) and 424 high-risk noncarriers (208 with breast/ovarian cancer). No differences between the male-to-female offspring ratios of all study groups were noted. Among mutation carriers, the offspring male-to-female ratio was 0.97 (444 : 460), and among mutation carriers with cancer it was 0.92 (262 : 284). Similarly, no offspring gender skewing was noted among high-risk noncarriers, regardless of health status. The rates of three or more spontaneous miscarriages among participants with at least one live birth were 4.37% (15/343) among mutation carriers and 3% (12/401) among high-risk women (P = not significant). In conclusion, the offspring gender ratio is similar in high-risk Jewish families and in the general population. The issue of the rate of recurrent miscarriages in high-risk Jewish women is unresolved.
15116316	130	135	BRCA1	Gene	672
15116316	136	141	BRCA2	Gene	675
15116316	283	288	BRCA1	Gene	672
15116316	351	356	BRCA1	Gene	672
15116316	357	362	BRCA2	Gene	675
15116316	545	550	BRCA1	Gene	672
15116316	551	556	BRCA2	Gene	675
15116316	714	719	BRCA1	Gene	672
15116316	720	725	BRCA2	Gene	675

15128701|t|Corticosteroid pharmacogenetics: association of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids.
15128701|a|Corticosteroids mediate a variety of immunological actions and are commonly utilized in the treatment of a wide range of diseases. Unfortunately, therapy with this class of medications is associated with a large proportion of non-responders and significant side effects. Inhaled corticosteroids are the most commonly used asthma controller therapy. However, asthmatic response to corticosteroids also varies widely between individuals. We investigated the genetic contribution to the variation in response to inhaled corticosteroid therapy in asthma. The association of longitudinal change in lung function and single nucleotide polymorphisms from candidate genes crucial to the biologic actions of corticosteroids were evaluated in three independent asthmatic clinical trial populations utilizing inhaled corticosteroids as the primary therapy in at least one treatment arm. Variation in one gene, corticotropin-releasing hormone receptor 1 (CRHR1) was consistently associated with enhanced response to therapy in each of our three populations. Individuals homozygous for the variants of interest manifested a doubling to quadrupling of the lung function response to corticosteroids compared with lack of the variants (P-values ranging from 0.006 to 0.025 for our three asthmatic populations). As the primary receptor mediating the release of adrenocorticotropic hormone, which regulates endogenous cortisol levels, CRHR1 plays a pivotal, pleiotropic role in steroid biology. These data indicate that genetic variants in CRHR1 have pharmacogenetic effects influencing asthmatic response to corticosteroids, provide a rationale for predicting therapeutic response in asthma and other corticosteroid-treated diseases, and suggests this gene pathway as a potential novel therapeutic target.
15128701	69	74	CRHR1	Gene	1394
15128701	1054	1096	corticotropin-releasing hormone receptor 1	Gene	1394
15128701	1098	1103	CRHR1	Gene	1394
15128701	1499	1526	adrenocorticotropic hormone	Gene	5443
15128701	1572	1577	CRHR1	Gene	1394
15128701	1677	1682	CRHR1	Gene	1394

15241479|t|A double cryptic chromosome imbalance is an important factor to explain phenotypic variability in Wolf-Hirschhorn syndrome.
15241479|a|A total of five Wolf-Hirschhorn syndrome (WHS) patient with a 4p16.3 de novo microdeletion was referred because of genotype-phenotype inconsistencies, first explained as phenotypic variability of the WHS. The actual deletion size was found to be about 12 Mb in three patients, 5 Mb in another one and 20 Mb in the last one, leading us to hypothesize the presence of an extrachromosome segment on the deleted 4p. A der(4)(4qter --> p16.1::8p23 --> pter) chromosome, resulting from an unbalanced de novo translocation was, in fact, detected in four patients and a der(4)(4qter --> q32::4p15.3 --> qter) in the last. Unbalanced t(4;8) translocations were maternal in origin, the rec(4p;4q) was paternal. With the purpose of verifying frequency and specificity of this phenomenon, we investigated yet another group of 20 WHS patients with de novo large deletions (n = 13) or microdeletions (n = 7) and with apparently straightforward genotype-phenotype correlations. The rearrangement was paternal in origin, and occurred as a single anomaly in 19 out of 20 patients. In the remaining patient, the deleted chromosome 4 was maternally derived and consisted of a der(4)(4qter --> 4p16.3::8p23 --> 8pter). In conclusions, we observed that 20% (5/25) of de novo WHS-associated rearrangements were maternal in origin and 80% (20/25) were paternal. All the maternally derived rearrangements were de novo unbalanced t(4;8) translocations and showed specific clinical phenotypes. Paternally derived rearrangements were usually isolated deletions. It can be inferred that a double, cryptic chromosome imbalance is an important factor for phenotypic variability in WHS. It acts either by masking the actual deletion size or by doubling a quantitative change of the genome.

15241482|t|Paraoxonase 1 polymorphisms and survival.
15241482|a|The antioxidant enzyme paraoxonase 1 (PON1) has previously been suggested to confer protection against coronary heart disease (CHD), one of the main causes of death in the Western world. Two coding polymorphisms, 55M/L and 192Q/R, and a promoter variant, -107C/T, has been extensively studied with respect to susceptibility to CHD. In this study, we have investigated the impact of these three polymorphisms on mortality using a sample of 1932 Danish individuals aged 47-93 years, previously used in gene-longevity studies. A cross-sectional study comparing the genotype distribution of the three polymorphisms separately as well as the haplotype distribution in different age groups did not reveal any difference. However, a longitudinal follow-up study on survival in the same sample indicated that 192RR homozygotes have a poorer survival compared to QQ homozygotes (hazard rate: 1.38, P = 0.04). We hereafter used an independent sample of 541 Danish individuals from the oldest cohort and confirmed the initial findings (hazard rate: 1.38, P = 0.09). In both samples, the effect was most pronounced in women. Using self-reported data on ischemic heart disease to evaluate the impact of the PON 192Q/R polymorphism on susceptibility to CHD, we found only a nonsignificant trend of 192RR homozygosity in women being a risk factor. Our results thus indicates that PON1 192RR homozygosity is associated with increased mortality in women in the second half of life and that this increased mortality is possibly related to CHD severity and survival after CHD rather than susceptibility to development of CHD.
15241482	0	13	Paraoxonase 1	Gene	5444
15241482	65	78	paraoxonase 1	Gene	5444
15241482	80	84	PON1	Gene	5444
15241482	1236	1239	PON	Gene	5444
15241482	1407	1411	PON1	Gene	5444

15252723|t|Trisomy 1 in a case of a missed abortion.
15252723|a|Most chromosomal trisomies lead to miscarriages. In all trisomies, trisomy 1 is the most rare case. We herein present a patient who demonstrated a gestational sac and a yolk sac on transvaginal ultrasound. However, at 53 days of gestation, the pregnancy was lost with a diagnosis of a blighted ovum. A D&C was recommended and performed. A cytogenetic analysis from chorionic villi demonstrated a 47,XX,+1 chromosome complement in all 100 cells. Regarding full trisomy 1, there has only been one case report of a preembryo and two case reports in a clinically recognized pregnancy to date.

15371903|t|CFTR mutation distribution among U.S. Hispanic and African American individuals: evaluation in cystic fibrosis patient and carrier screening populations.
15371903|a|PURPOSE: We reviewed CFTR mutation distribution among Hispanic and African American individuals referred for CF carrier screening and compared mutation frequencies to those derived from CF patient samples. METHODS: Results from CFTR mutation analyses received from January 2001 through September 2003, were analyzed for four populations: Hispanic individuals with a CF diagnosis (n = 159) or carrier screening indication (n = 15,333) and African American individuals with a CF diagnosis (n = 108) or carrier screening indication (n = 8,973). All samples were tested for the same 87 mutation panel. RESULTS: In the Hispanic population, 42 mutations were identified: 30 in the patient population (77.5% detection rate) and 33 among carrier screening referrals. Five mutations not included in the ACMG/ACOG carrier screening panel (3876delA, W1089X, R1066C, S549N, 1949del84) accounted for 7.55% detection in patients and 5.58% among carriers. Among African American referrals, 33 different mutations were identified: 21 in the patient population (74.4% detection) and 23 in the carrier screening population. Together, A559T and 711+5G>A were observed at a detection rate of 3.71% in CF patients and 6.38% in carriers. The mutation distribution seen in both the carrier screening populations reflected an increased frequency of mutations with variable expression such as D1152H, R117H, and L206W. CONCLUSIONS: A detailed analysis of CFTR mutation distribution in the Hispanic and African American patient and carrier screening populations demonstrates that a diverse group of mutations is most appropriate for diagnostic and carrier screening in these populations. To best serve the increasingly diverse U.S. population, ethnic-specific mutations should be included in mutation panels.
15371903	0	4	CFTR	Gene	1080
15371903	175	179	CFTR	Gene	1080
15371903	382	386	CFTR	Gene	1080
15371903	1584	1588	CFTR	Gene	1080

15459975|t|Fine mapping and identification of a candidate gene SSH1 in disseminated superficial actinic porokeratosis.
15459975|a|Disseminated superficial actinic porokeratosis (DSAP) is an uncommon autosomal dominant chronic keratinization disorder, characterized by multiple superficial keratotic lesions surrounded by a slightly raised keratotic border. Thus far, although two loci for DSAP have been identified, the genetic basis and pathogenesis of this disorder have not been elucidated yet. In this study, we performed a genome-wide linkage analysis in three Chinese affected families and localized the gene in an 8.0 cM interval defined by D12S330 and D12S354 on chromosome 12. Upon screening 30 candidate genes, we identified a missense mutation, p.Ser63Asn in SSH1 in one family, a frameshift mutation, p.Ser19CysfsX24 in an alternative variant (isoform f) of SSH1 in another family, and a frameshift mutation, p.Pro27ProfsX54 in the same alternative variant in one non-familial case with DSAP. SSH1 encodes a phosphatase that plays a pivotal role in actin dynamics. Our data suggested that cytoskeleton disorganization in epidermal cells is likely associated with the pathogenesis of DSAP.
15459975	52	56	SSH1	Gene	54434
15459975	748	752	SSH1	Gene	54434
15459975	848	852	SSH1	Gene	54434
15459975	983	987	SSH1	Gene	54435

15480879|t|Alternative splicing in the N-terminus of Alzheimer's presenilin 1.
15480879|a|Presenilin 1 (PS1) is mutated in the majority of familial cases of Alzheimer disease (AD). Although it is clear that PS1 is involved in the processing of the amyloid precursor protein (APP), the exact function of PS1 is still elusive. Human presenilin 1 (PS1) is alternatively spliced, resulting in the presence or absence of a four-amino acid motif, VRSQ, in the PS1 N-terminus. In human tissues, both isoforms are expressed. Here we report that mouse and rat only express the longer PS1 isoform. The presence of this motif introduces a potential phosphorylation site for protein kinase C. Because the splice occurs in the region of PS1 that we have previously shown to bind to rabGDI, this might provide a regulatory mechanism for this interaction. Our data show that the -VRSQ isoform binds rabGDI, but the +VRSQ does not. Moreover, mutation of the putatively phosphorylated threonine in PS1 disrupts the binding to rabGDI, showing its importance for the interaction. To our knowledge this is the first study showing a functional difference between PS1 splice variants. The possible consequences for APP processing and the pathogenesis of AD are discussed.
15480879	54	66	presenilin 1	Gene	5663
15480879	68	80	Presenilin 1	Gene	5663
15480879	82	85	PS1	Gene	5663
15480879	185	188	PS1	Gene	5663
15480879	281	284	PS1	Gene	5663
15480879	309	321	presenilin 1	Gene	5663
15480879	323	326	PS1	Gene	5663
15480879	432	435	PS1	Gene	5663
15480879	553	556	PS1	Gene	19164
15480879	553	556	PS1	Gene	5663
15480879	641	657	protein kinase C	Gene	-1
15480879	702	705	PS1	Gene	-1
15480879	747	753	rabGDI	Gene	-1
15480879	862	868	rabGDI	Gene	-1
15480879	959	962	PS1	Gene	5663
15480879	987	993	rabGDI	Gene	-1
15480879	1120	1123	PS1	Gene	5663

15523499|t|Haplotype structure of the beta adrenergic receptor genes in US Caucasians and African Americans.
15523499|a|The beta-adrenergic receptors (beta-AR) are G protein-coupled receptors activated by epinephrine and norepinephrine and are involved in a variety of their physiological functions. Previously, three beta-AR genes (ADRB1, ADRB2 and ADRB3) were resequenced, identifying polymorphisms that were used in genetic association studies of cardiovascular and metabolic disorders. These studies have produced intriguing but inconsistent results, potentially because the known functional variants: ADRB1 Arg389Gly and Gly49Ser, ADRB2 Arg16Gly and Gln27Glu, and ADRB3 Arg64Trp provided an incomplete picture of the total functional diversity at these genes. Therefore, we created marker panels for each beta-AR gene that included the known functional markers and also other markers evenly spaced and with sufficient density to identify haplotype block structure and to maximize haplotype diversity. A total of 27 markers were genotyped in 96 US Caucasians and 96 African Americans. In both populations and for each gene, a single block with little evidence of historical recombination was observed. For each gene, haplotype captured most of the information content of each functional locus, even if that locus was not genotyped, and presumably haplotype would capture the signal from unknown functional loci whose alleles are of moderate abundance. This study demonstrates the utility of using beta-AR gene haplotype maps and marker panels as tools for linkage studies on beta-AR function.
15523499	311	316	ADRB1	Gene	153
15523499	318	323	ADRB2	Gene	154
15523499	328	333	ADRB3	Gene	155
15523499	584	589	ADRB1	Gene	153
15523499	614	619	ADRB2	Gene	154
15523499	647	652	ADRB3	Gene	155

15530539|t|Cis-acting transmission of genomic instability.
15530539|a|Genomic instability is a highly pleiotropic phenotype, which may reflect a variety of underlying mechanisms. Destabilization has been shown in some cases to involve mutational alteration or inactivation of trans-acting cellular factors, for example, p53 or mismatch repair functions. However, aspects of instability are not well explained by mutational inactivation of trans-acting factors, and other epigenetic and cis-acting mechanisms have recently been proposed. The trans and cis models result in divergent predictions for the distribution of instability-associated genetic alterations within the genome, and for the inheritance of genomic instability among sibling sub-clones of unstable parents. These predictions have been tested in this study primarily by tracking the karyotypic distribution of chromosomal rearrangements in clones and sub-clones exhibiting radiation-induced genomic instability; inheritance of mutator phenotypes was also analyzed. The results indicate that genomic instability is unevenly transmitted to sibling sub-clones, that chromosomal rearrangements within unstable clones are non-randomly distributed throughout the karyotype, and that the majority of chromosomal rearrangements associated with instability affect trisomic chromosomal segments. Observations of instability in trisomic regions suggests that in addition to promoting further alterations in chromosomal number, aneuploidy can affect the recovery of structural rearrangements. In summary, these findings cannot be fully explained by invoking a homogeneously distributed factor acting in trans, but do provide support for previous suggestions that genomic instability may in part be driven by a cis-acting mechanism.
15530539	298	301	p53	Gene	7157

15583840|t|Tumor associated antigen recognition by autologous serum in patients with breast cancer.
15583840|a|Breast cancer accounts for 30-40% of all deaths from cancers in females. In an effort to identify tumor associated antigens that may be useful for immunotherapy, we utilized serological analysis of recombinant cDNA expression libraries (SEREX) technique to identify breast cancer-associated antigens. SEREX screening of cDNA expression libraries derived from 3 breast cancer patients identified a total of 88 positive clones (bcg-1 to bcg-88), including 27 hitherto unknown sequences. The cDNA sequences and mRNA expression patterns were characterized. Seroreactivity of the SEREX clones were determined in sera from 75 breast cancer patients, 75 colon cancer patients, and 25 healthy donors. Expression analysis on a cDNA panel from 17 different normal tissues by reverse transcription-PCR (RT-PCR) revealed tissue restricted mRNA expression of 2 of the 27 unknown antigens. Bcg-72 is expressed only in breast, prostate and thymus, while bcg-84 is expressed at moderate levels in testis, spleen and breast. The other 25 unknown antigens were expressed in most other tissues. Serologic assay revealed that 7 out of the 88 clones showed reactivity to at least one serum from either 75 breast or 75 colon cancer patients. These clones did not react with sera from a panel of 25 healthy adult individuals. Our results demonstrate the utility of the SEREX approach for the identification of potential tumor associated antigens in human breast cancer.
15583840	515	530	bcg-1 to bcg-88	Gene	-1
15583840	965	971	Bcg-72	Gene	-1
15583840	1028	1034	bcg-84	Gene	-1

15689448|t|Automated genomic sequence analysis of the three collagen VI genes: applications to Ullrich congenital muscular dystrophy and Bethlem myopathy.
15689448|a|INTRODUCTION: Mutations in the genes encoding collagen VI (COL6A1, COL6A2, and COL6A3) cause Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD). BM is a relatively mild dominantly inherited disorder with proximal weakness and distal joint contractures. UCMD is an autosomal recessive condition causing severe muscle weakness with proximal joint contractures and distal hyperlaxity. METHODS: We developed a method for rapid direct sequence analysis of all 107 coding exons of the COL6 genes using single condition amplification/internal primer (SCAIP) sequencing. We have sequenced all three COL6 genes from genomic DNA in 79 patients with UCMD or BM. RESULTS: We found putative mutations in one of the COL6 genes in 62% of patients. This more than doubles the number of identified COL6 mutations. Most of these changes are consistent with straightforward autosomal dominant or recessive inheritance. However, some patients showed changes in more than one of the COL6 genes, and our results suggest that some UCMD patients may have dominantly acting mutations rather than recessive disease. DISCUSSION: Our findings may explain some or all of the cases of UCMD that are unlinked to the COL6 loci under a recessive model. The large number of single nucleotide polymorphisms which we generated in the course of this work may be of importance in determining the major phenotypic variability seen in this group of disorders.
15689448	203	209	COL6A1	Gene	1291
15689448	211	217	COL6A2	Gene	1292
15689448	223	229	COL6A3	Gene	1293

15748645|t|Photochemoprevention of ultraviolet B signaling and photocarcinogenesis.
15748645|a|Exposure to solar radiation, particularly its ultraviolet (UV) B component, has a variety of harmful effects on human health. Some of these effects include sunburn cell formation, basal and squamous cell cancers, melanoma, cataracts, photoaging of the skin, and immune suppression. Amongst these various adverse effects of UV radiation, skin cancer is of the greatest concern. Over the years, changes in lifestyle has led to a significant increase in the amount of UV radiation that people receive, and this consequently has led to a surge in the incidence of skin cancer. The development of skin cancer is a complex multistage phenomenon involving three distinct stages exemplified by initiation, promotion and progression stages. Each of these stages is mediated via alterations in various cellular, biochemical, and molecular changes. Initiation, the first step in the carcinogenesis process is essentially an irreversible step in which genetic alterations occur in genes that ultimately leads to DNA modification and fixation of mutation. Tumor promotion is the essential process in cancer development involving clonal expansion of initiated cells giving rise to pre-malignant and then to malignant lesions, essentially by alterations in signal transduction pathways. Tumor progression involves the conversion of pre-malignant and malignant lesions into an invasive and potentially metastatic malignant tumor. All these processes for skin cancer development involve stimulation of DNA synthesis, DNA damage and proliferation, inflammation, immunosuppression, epidermal hyperplasia, cell cycle dysregulation, depletion of antioxidant defenses, impairment of signal transduction pathways, induction of cyclooxygenase, increase in prostaglandin synthesis, and induction of ornithine decarboxylase. Photochemoprevention has been appreciated as a viable approach to reduce the occurrence of skin cancer and in recent years, the use of agents, especially botanical antioxidants, present in the common diet and beverages consumed by human population have gained considerable attention as photochemopreventive agents for human use. Many such agents have also found a place in skin care products. Although this is more common in oriental countries, its popularity is significantly growing in western countries. In this article, we have summarized the available information of laboratory studies on UVB-mediated signaling that can be exploited as targets for photochemoprevention. We suggest that the use of skin care products supplemented with proven chemopreventive agents in conjunction with the use of sunscreens along with educational efforts may be an effective strategy for reducing UV-induced photodamage and skin cancer in humans. The mechanistic basis for the use of such products is discussed.
15748645	1847	1870	ornithine decarboxylase	Gene	4953

15823919|t|Molecular genetic and ocular findings in patients with holt-oram syndrome.
15823919|a|PURPOSE: The autosomal dominant Holt-Oram syndrome (HOS) is characterized by upper limb and cardiac septal defects. Mutations of the TBX5 gene have been identified as the underlying gene defect in HOS. Embryonic expression of TBX5 has been found in the human retina. This is the first report of ocular findings in two unrelated families with mutations in the TBX5 gene. METHODS: Six living persons affected with HOS and 10 unaffected family members were subjected to mutation analysis and complete ophthalmological examination, including electrophysiological examinations (EOG and flash ERG). RESULTS: A heterozygous single base-pain substitution in exon 5 (408C --> A) was detected in all affected patients. All examined affected patents were ophthalmological asymptomatic with normal EOG. A scotopic elongated b-wave latency was found in affected family members who were older than 35 years. The ERG was normal in the young patients. CONCLUSIONS: Haploinsufficiency of TBX5 alters the dorsal-ventral polarity in developing eye vesicles without amy detected functional loss in human. Slight ERG abnormalities later in life may be a result of changes induced by the inner ganglion cell layer in the inner nuclear layer.
15823919	208	212	TBX5	Gene	6910
15823919	301	305	TBX5	Gene	6910
15823919	434	438	TBX5	Gene	6910
15823919	1046	1050	TBX5	Gene	6910

15834508|t|Low RET mutation frequency and polymorphism analysis of the RET and EDNRB genes in patients with Hirschsprung disease in Taiwan.
15834508|a|Hirschsprung disease (HSCR), or congenital intestinal aganglionosis, is a relatively common disorder characterized by the absence of ganglion cells in the nerve plexuses of the lower digestive tract, resulting in intestinal obstruction in neonates. Mutations in genes of the RET receptor tyrosine kinase and endothelin receptor B (EDNRB) signaling pathways have been shown to be associated in HSCR patients. In this study, we collected genomic DNA samples from 55 HSCR patients in central Taiwan and analyzed the coding regions of the RET and EDNRB genes by PCR amplification and DNA sequencing. In the 55 patients, an A to G transition was detected in two (identical twin brothers). The mutation was at the end of RET exon 19 at codon 1062 (Y1062C), a reported critical site for the signaling pathways. Single nucleotide polymorphisms (SNP) in exons 2, 7, 11, 13, and 15 of RET and exon 4 of EDNRB in the HSCR patients or controls were detected. The differences between patients and controls in allele distribution of the five RET polymorphic sites were statistically significant. The most frequent genotype encompassing exons 2 and 13 SNPs (the polymorphic sites with the highest percentage of heterozygotes) was AA/GG in patients, which was different from the AG/GT in the normal controls. Transmission disequilibrium was observed in exons 2, 7, and 13, indicating nonrandom association of the susceptibility alleles with the disease in the patients. This study represents the first comprehensive genetic analysis of HSCR disease in Taiwan.
15834508	4	7	RET	Gene	5979
15834508	60	63	RET	Gene	5979
15834508	68	73	EDNRB	Gene	1910
15834508	404	407	RET	Gene	5979
15834508	408	432	receptor tyrosine kinase	Gene	5979
15834508	437	458	endothelin receptor B	Gene	1910
15834508	460	465	EDNRB	Gene	1910
15834508	664	667	RET	Gene	5979
15834508	672	677	EDNRB	Gene	1910
15834508	844	847	RET	Gene	5979
15834508	1004	1007	RET	Gene	5979
15834508	1022	1027	EDNRB	Gene	1910
15834508	1157	1160	RET	Gene	5979

15838180|t|Superimposing polymorphism: the case of a point mutation within a polymorphic Alu insertion.
15838180|a|The COL3A1 Alu insertion is a member of the AluY subfamily. It has been found to be absent in non-human primates and polymorphic in worldwide human populations. The integration of the element into the human genome seems to have preceded the initial migration(s) of anatomically modern humans out of the African continent. Although the insertion has been detected in populations from all the continents, its highest frequency values are located within sub-Saharan Africa. The sequence alignment of the COL3A1 insertion from several African individuals revealed a bi-allelic single nucleotide polymorphism (SNP) at the downstream terminus of the element's poly-A tract. Once discovered, a selective PCR procedure was designed to determine the frequency of both alleles in 19 worldwide populations. The A-allele in this binary SNP experiences a clinal increase in the eastward direction from Africa to Southeast Asia and Mongolia, reaching fixation in the two latter regions. The T variant, on the other hand, exhibits a westward clinal increase outside of Africa, with its lowest frequency in Asia and achieving fixation in northern Europe. The presence of this internal SNP extends the usefulness provided by the polymorphic Alu insertion (PAI). It is possible that superimposing polymorphisms like this one found in the COL3A1 locus may accentuate signals from genetic drift events allowing for visualization of recent dispersal patterns.
15838180	97	103	COL3A1	Gene	1281
15838180	594	600	COL3A1	Gene	1281
15838180	1413	1419	COL3A1	Gene	1281

15860362|t|Burkitt-type acute leukemia in a patient with B-prolymphocytic leukemia: evidence for a common origin.
15860362|a|Burkitt-type acute leukemia cells were present in the bone marrow of a patient with B-prolymphocytic leukemia diagnosed from peripheral blood cell morphology. Immunophenotype analysis confirmed morphological patterns. Cytogenetic and fluorescence in situ hybridization (FISH) analysis showed an identical t(8;22)(q24;q21) with MYC locus rearrangement in blood and bone marrow cells, with additional chromosome abnormalities in the bone marrow. In addition, the loss of one copy of the TP53 gene and identical IGH DNA clonal rearrangements were shown with FISH and polymerase chain reaction analysis respectively in the two types of leukemic cells. These data indicated the common origin of the two coexisting leukemias and are the first example of such occurrence in a leukemic patient.
15860362	430	433	MYC	Gene	4609
15860362	588	592	TP53	Gene	7157
15860362	612	615	IGH	Gene	3492

15864130|t|Haplotypes of variants in the UDP-glucuronosyltransferase1A9 and 1A1 genes.
15864130|a|OBJECTIVES: Nine different functional UGT1A enzymes are generated from a single UGT1A gene by alternative splicing, with each enzyme having a unique exon 1. SN-38, the active metabolite of the anticancer agent irinotecan, is metabolized by both UGT1A1 and UGT1A9. We aim to characterize the UGT1A9-UGT1A1 haplotypes in Asians and Caucasians and gain insights on their functional consequences. METHODS: Asian and Caucasian individuals were genotyped for UGT1A1 and UGT1A9 variants. RESULTS: A higher frequency of the UGT1A9 -118T10 allele was observed in Asians compared to Caucasians, while the -275T>A and -2152C>T variants were relatively uncommon in Caucasians and not found in Asians. The strongest linkage disequilibrium (LD) was observed between the UGT1A1 -53 and -3156 and between the UGT1A9 -275 and -2152 loci. Lower LD was observed between the -118 UGT1A9 variant and the UGT1A1 variants. Fourteen UGT1A9-UGT1A1 haplotypes were found in Asians, seven of them found to be shared by both populations. Common UGT1A9-UGT1A1 diplotypes were defined, and a difference was observed across the SN-38 glucuronidation rates in Caucasian livers stratified by diplotypes. CONCLUSION: This study for the first time described common UGT1A9-UGT1A1 haplotypes, highlighting important ethnic differences between Asians and Caucasians. If the functional effect of these haplotypes can be confirmed, this haplotypic information would be applicable to the correct design of prospective clinical studies of irinotecan, as well as of other drugs primarily metabolized by both UGT1A1 and UGT1A9.
15864130	30	60	UDP-glucuronosyltransferase1A9	Gene	54600
15864130	30	68	UDP-glucuronosyltransferase1A9 and 1A1	Gene	54658
15864130	114	119	UGT1A	Gene	7361
15864130	156	161	UGT1A	Gene	7361
15864130	321	327	UGT1A1	Gene	54658
15864130	332	338	UGT1A9	Gene	54600
15864130	367	373	UGT1A9	Gene	54600
15864130	374	380	UGT1A1	Gene	54658
15864130	529	535	UGT1A1	Gene	54658
15864130	540	546	UGT1A9	Gene	54600
15864130	592	598	UGT1A9	Gene	54600
15864130	832	838	UGT1A1	Gene	54658
15864130	869	875	UGT1A9	Gene	54600
15864130	936	942	UGT1A9	Gene	54600
15864130	959	965	UGT1A1	Gene	54658
15864130	985	991	UGT1A9	Gene	54600
15864130	992	998	UGT1A1	Gene	54658
15864130	1093	1099	UGT1A9	Gene	54600
15864130	1100	1106	UGT1A1	Gene	54658
15864130	1306	1312	UGT1A9	Gene	54600
15864130	1313	1319	UGT1A1	Gene	54658
15864130	1641	1647	UGT1A1	Gene	54658
15864130	1652	1658	UGT1A9	Gene	54600

15899389|t|Identification of a transcriptionally active hVH-5 pseudogene on 10q22.2.
15899389|a|Mitogen-activated protein kinases (MAPKs) are important regulators of a vast number of biological functions that affect life and death of eukaryotic cells and are tightly regulated by the concerted action of several phosphatases. Among these is the human homologue of vaccinia virus H1 phosphatase gene clone 5 (hVH-5) product, which dephosphorylates and thus inhibits members of the MAPK family. Here, we analyzed hVH-5 transcripts in mammary carcinoma cell lines and discovered a sequence with 88% similarity to hVH-5 transcripts. Because this variant of hVH-5 lacked intronic sequences in its genomic structure, we suggest it might be a processed pseudogene of hVH-5. psihVH-5 transcripts were detected in human peripheral tissues as well as in 11 of 14 breast cancer cell lines. In respect to the normal hVH-5 gene, the pseudogene contains several point mutations and a frame shift due to the deletion of 2 bases that would lead to the truncation of the putative psihVH-5 product.
15899389	45	50	hVH-5	Gene	1850
15899389	342	384	vaccinia virus H1 phosphatase gene clone 5	Gene	1850
15899389	386	391	hVH-5	Gene	1850
15899389	489	494	hVH-5	Gene	1850
15899389	588	593	hVH-5	Gene	1850
15899389	631	636	hVH-5	Gene	1850
15899389	738	743	hVH-5	Gene	1850
15899389	882	887	hVH-5	Gene	1850

15970799|t|Functional characterization of SLCO1B1 (OATP-C) variants, SLCO1B1*5, SLCO1B1*15 and SLCO1B1*15+C1007G, by using transient expression systems of HeLa and HEK293 cells.
15970799|a|OBJECTIVES: SLCO1B1*5 and SLCO1B1*15 have been reported to reduce the clearance of pravastatin in healthy volunteers. However, there remains controversy in the effects of SLCO1B1*5 on the activity of OATP1B1 in vitro. In addition, the effect of SLCO1B1*15 on the function of OATP1B1 has not been studied using cDNA-expression systems. Object of the present study was to study the influence of SLCO1B1*5, *15 and *15+C1007G, a novel haplotype found in a patient with pravastatin-induced myopathy, on the functional properties of OATP1B1 by transient expression systems of HEK293 and HeLa cells using endogenous conjugates and statins as substrates. METHODS: Transporting assays for endogenous substrates were performed using tritium labeled estradiol-17beta-D-glucuronide and estrone-3-sulfate. Quantitation of pravastatin, atorvastatin, cerivastatin and simvastatin were carried out using HPLC tandem mass spectrometry. RESULTS: The transporting activities of cells expressing SLCO1B1*5, *15 and *15+C1007G decreased significantly but those of SLCO1B1*1b, *1a+C1007G and *1b+C1007G were not altered for all of the substrates tested except for simvastatin. Kinetic analysis of pravastatin and atorvastatin showed that Km values were not altered but Vmax values decreased significantly in cells expressing SLCO1B1*5, *15 and *15+C1007G. Immunocytochemical study showed that SLCO1B1*5, *15 and *15+C1007G proteins are localized not only at the plasma membrane but also in the intracellular space. CONCLUSIONS: These findings suggest that 521T>C, existing commonly in SLCO1B1*5, *15 and *15+C1007G, is the key single nucleotide polymorphism (SNP) that determines the functional properties of SLCO1B1*5, *15 and *15+C1007G allelic proteins and that decreased activities of these variant proteins are mainly caused by a sorting error produced by this SNP.
15970799	31	38	SLCO1B1	Gene	10599
15970799	40	46	OATP-C	Gene	10599
15970799	58	65	SLCO1B1	Gene	10599
15970799	69	76	SLCO1B1	Gene	10599
15970799	84	91	SLCO1B1	Gene	10599
15970799	179	186	SLCO1B1	Gene	10599
15970799	193	200	SLCO1B1	Gene	10599
15970799	338	345	SLCO1B1	Gene	10599
15970799	367	374	OATP1B1	Gene	10599
15970799	412	419	SLCO1B1	Gene	10599
15970799	442	449	OATP1B1	Gene	10599
15970799	560	567	SLCO1B1	Gene	10599
15970799	695	702	OATP1B1	Gene	10599
15970799	1144	1151	SLCO1B1	Gene	10599
15970799	1211	1218	SLCO1B1	Gene	10599
15970799	1471	1478	SLCO1B1	Gene	10599
15970799	1539	1546	SLCO1B1	Gene	10599
15970799	1731	1738	SLCO1B1	Gene	10599
15970799	1855	1862	SLCO1B1	Gene	10599

16021854|t|The effect of exogenous estradiol treatment on the mRNA expression of vascular endothelial growth factor and its receptors in cultured human oviduct mucosal cells.
16021854|a|PURPOSE: To evaluate the responses of cultured oviduct mucosal cells to exogenous estradiol treatment in regulating the mRNA expression of vascular endothelial growth factor (VEGF) and its receptors. METHODS: The mucosal layer of the ampullary regions of the human oviduct was isolated and cultured with (study groups) or without (control group) the addition of exogenous estradiol in five different concentrations. Semiquantitative reverse-transcriptase-polymerase chain reaction was performed on the oviduct mucosal cells before and after the 6-day culture. RESULTS: There were no significant differences in the mRNA expression of VEGF and its receptors, both KDR and flt-1, between the five study groups and the control group. CONCLUSIONS: The mRNA expression of VEGF and its receptors is not altered by exogenous estradiol treatment in cultured oviduct. This helps to explain the mechanism of temporal regulation of VEGF in human oviduct, which reaches the peak level in the peri-ovulatory stage when both the serum estradiol and gonadotropins concentrations are high.
16021854	70	104	vascular endothelial growth factor	Gene	7422
16021854	303	337	vascular endothelial growth factor	Gene	7422
16021854	339	343	VEGF	Gene	7422
16021854	797	801	VEGF	Gene	7422
16021854	826	829	KDR	Gene	3792
16021854	834	839	flt-1	Gene	2321
16021854	930	934	VEGF	Gene	7422
16021854	1084	1088	VEGF	Gene	7422

16047583|t|Luteal phase serum cell-free DNA as a marker of failed pregnancy after assisted reproductive technology.
16047583|a|PURPOSE: DNA-damaging factors have been reported in patients that failed to achieve pregnancy after assisted reproductive technologies (ART). The hypothesis was that increased circulating cell-free DNA released by damaged cells could predict unfavorable conditions leading to failed ART treatment. The objective was to compare the relative concentrations of cell-free DNA in the luteal phase sera of nonpregnant versus pregnant patients. METHODS: Frozen-thawed sera (30 IVF cases) were obtained 1 week after embryo transfer. There were 16 pregnant and 14 nonpregnant cases and controls consisting of male sera (n = 8 cases). Modified isocratic capillary electrophoresis was performed and the images analyzed for cell-free DNA. RESULTS: Circulating cell-free DNA were identified in the sera of all patients. The serum concentrations of high (12 kb) and low (1 kb) molecular weight cell-free DNA were similar for both nonpregnant and pregnant patients. Male control sera had higher cell-free DNA concentrations compared with females. Evaluation of sera from a control case showed no fluctuations in cell-free DNA concentrations throughout specific days of the menstrual cycle. CONCLUSIONS: The results do not support the use of the luteal phase cell-free DNA concentration as a marker for failed pregnancies. The equal concentrations of high and low molecular weight cell-free DNA and ladder band-like gel patterns suggested cell apoptosis as the source of DNA.

16114047|t|Acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome: report of a child with phenotypic overlap with ulnar-mammary syndrome and a new mutation in TP63.
16114047|a|We report on a new patient with clinical findings consistent with acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome. The child had sparse hair, extensive freckling, lacrimal duct stenosis, oligodontia, dystrophic nails, reduced sweating, and bilateral athelia. Examination of his hands showed ulnar ray hypoplasia with bilateral fifth finger brachydactyly and camptodactyly. He also had surgical repair of an imperforate anus. Mutation analysis of TP63 showed a single nucleotide substitution, c.G518A, predicting a novel missense mutation, p.V114M in exon 4. This is the third mutation to be reported in TP63 in ADULT syndrome.
16114047	145	149	TP63	Gene	8626
16114047	601	605	TP63	Gene	8626
16114047	758	762	TP63	Gene	8626

16158428|t|Delineation of the clinical phenotype associated with OPHN1 mutations based on the clinical and neuropsychological evaluation of three families.
16158428|a|Recent reports have demonstrated that mutations in the OPHN1 gene were responsible for a syndromic rather than non-specific mental retardation. Abnormalities of the posterior fossa with cerebellar hypoplasia have been demonstrated in all male patients reported to date. We report here a new family with X-linked mental retardation due to mutation in OPHN1 and present unpublished data about two families previously reported, concerning the facial and psychological phenotype of affected males and carrier females. Our study confirms that cerebellar hypoplasia is a hallmark of this syndrome. In addition, affected males display facial similarities that can help the diagnosis. Most carrier females have mild mental retardation and subtle facial changes.
16158428	54	59	OPHN1	Gene	4983
16158428	200	205	OPHN1	Gene	4983
16158428	495	500	OPHN1	Gene	4983

16179221|t|Application of a comprehensive subtelomere array in clinical diagnosis of mental retardation.
16179221|a|In 2-8% of patients with mental retardation, small copy number changes in the subtelomeric region are thought to be the underlying cause. As detection of these genomic rearrangements is labour intensive using FISH, we constructed and validated a high-density BAC/PAC array covering the first 5 Mb of all subtelomeric regions and applied it in our routine screening of patients with idiopathic mental retardation for submicroscopic telomeric rearrangements. The present study shows the efficiency of this comprehensive subtelomere array in detecting terminal deletions and duplications but also small interstitial subtelomeric rearrangements, starting from small amounts of DNA. With our array, the size of the affected segments, at least those smaller than 5 Mb, can be determined simultaneously in the same experiment. In the first 100 patient samples analysed in our diagnostic practice by the use of this comprehensive telomere array, we found three patients with deletions in 3p, 10q and 15q, respectively, four patients with duplications in 9p, 12p, 21q and Xp, respectively, and one patient with a del 6q/dup 16q. The patients with del 3p and 10q and dup 12p had interstitial rearrangements that would have been missed with techniques using one probe per subtelomeric region chosen close to the telomere.

16247291|t|NSD1 analysis for Sotos syndrome: insights and perspectives from the clinical laboratory.
16247291|a|PURPOSE: Sotos syndrome is a genetic disorder characterized primarily by overgrowth, developmental delay, and a characteristic facial gestalt. Defects in the NSD1 gene are present in approximately 80% of patients with Sotos syndrome. The goal of this study was to determine the incidence of NSD1 abnormalities in patients referred to a clinical laboratory for testing and to identify clinical criteria that distinguish between patients with and without NSD1 abnormalities. METHODS: Deletion or mutation analysis of the NSD1 gene was performed on 435 patients referred to our clinical genetics laboratory. Detailed clinical information was obtained on 86 patients with and without NSD1 abnormalities, and a clinical checklist was developed to help distinguish between these two groups of patients. RESULTS: Abnormalities of the NSD1 gene were identified in 55 patients, including 9 deletions and 46 mutations. Thus, in the clinical laboratory setting, deletions were found in 2% and mutations in 21% of samples analyzed, because not all patients had both tests. Thirty-three previously unreported mutations in the NSD1 gene were identified. Clinical features typically associated with Sotos syndrome were not found to be significantly different between individuals with and without NSD1 abnormalities. The clinical checklist developed included poor feeding, increased body mass index, and enlarged cerebral ventricles, in addition to the typical clinical features of Sotos syndrome, and was able to distinguish between the two groups with 80% sensitivity and 70% specificity. CONCLUSIONS: The dramatic decrease in the frequency of finding NSD1 abnormalities in the clinical laboratory is likely because of the heterogeneity of the patient population. Our experience from a diagnostic laboratory can help guide clinicians in deciding for whom NSD1 genetic analysis is indicated.
16247291	0	4	NSD1	Gene	64324
16247291	248	252	NSD1	Gene	64324
16247291	381	385	NSD1	Gene	64324
16247291	543	547	NSD1	Gene	64324
16247291	609	613	NSD1	Gene	64324
16247291	770	774	NSD1	Gene	64324
16247291	917	921	NSD1	Gene	64324
16247291	1203	1207	NSD1	Gene	64324
16247291	1371	1375	NSD1	Gene	64324
16247291	1728	1732	NSD1	Gene	64324
16247291	1931	1935	NSD1	Gene	64324

16271961|t|Rarity of IgH translocations in Waldenström macroglobulinemia.
16271961|a|Comparatively little is known of the cytogenetics of Waldenström macroglobulinemia (WM). This is primarily due to the low proliferation of the clonal B cells, which precludes conventional karyotyping in many cases. Translocations involving the immunoglobulin heavy chain (IGH) gene at 14q32 are characteristic of many B-cell lymphomas and myelomas. Initial reports suggested that the t(9;14) was characteristic of lymphoplasmacytic lymphoma (the underlying pathological diagnosis in WM), but subsequent studies have failed to confirm the uniqueness of the translocation. To clarify this, we examined 69 cases of WM with interphase fluorescence in situ hybridization and failed to demonstrate an IgH translocation in 67 (97%). We conclude that IGH translocations are not a feature of WM, and the implications of this finding are discussed.
16271961	10	13	IgH	Gene	3492
16271961	309	335	immunoglobulin heavy chain	Gene	3495
16271961	337	340	IGH	Gene	3495
16271961	760	763	IgH	Gene	3492
16271961	808	811	IGH	Gene	3495

16273295|t|IL-1 receptor antagonist attenuates MAP kinase/AP-1 activation and MMP1 expression in UVA-irradiated human fibroblasts induced by culture medium from UVB-irradiated human skin keratinocytes.
16273295|a|Solar UV light comprises UVB wavelengths (290-320 nm) and UVA wavelengths (320-400 nm). UVB radiation reaches the epidermis and, to a lesser extent, the upper part of the dermis, while UVA radiation penetrates more deeply into human skin. Existing studies have demonstrated that UV-irradiated epidermal keratinocytes release cytokines that indirectly promote MMP-1 production in dermal fibroblasts. In this study, we first investigated the effect of IL-1 on MAPK activity, c-Jun and c-Fos mRNA expression, and MMP-1 and MMP-2 production in UVA-irradiated human dermal fibroblasts. The results showed that UVA irradiation dose-dependently increased MMP-1 but not MMP-2 production in human skin fibroblasts. IL-1alpha and IL-1beta promoted MMP-1 but not MMP-2 production in UVA-irradiated fibroblasts. Both IL-1alpha and IL-1beta activated MAP kinase, significantly elevating c-Jun and c-Fos mRNA expression. We then investigated the indirect effect of UVB-irradiated keratinocyte culture medium on MMP-1 production in UVA-irradiated primary cultured human dermal fibroblasts and the effect of IL-1Ra. The results showed that cell culture medium from UVB-irradiated keratinocytes increased MMP-1 production in UVA-irradiated fibroblasts, and IL-1Ra dose-dependently inhibited MMP-1 production. IL-1Ra dose-dependently inhibited c-Jun mRNA expression of fibroblasts with no significant effect on c-Fos mRNA expression. These results demonstrate that UVB-irradiated keratinocytes promoted MMP-1 production in UVA-irradiated fibroblasts in a paracrine manner while IL-1Ra reduced MMP-1 production through inhibiting c-Jun mRNA expression. Collectively, our data suggest that IL-1 plays an important role in the dermal collagen degradation associated with UV-induced premature aging of the skin and IL-1Ra may be applied for the prevention and treatment of photoaging.
16273295	0	24	IL-1 receptor antagonist	Gene	3557
16273295	36	46	MAP kinase	Gene	-1
16273295	47	51	AP-1	Gene	-1
16273295	67	71	MMP1	Gene	4312
16273295	550	555	MMP-1	Gene	4312
16273295	641	645	IL-1	Gene	3553
16273295	649	653	MAPK	Gene	-1
16273295	664	669	c-Jun	Gene	3725
16273295	674	679	c-Fos	Gene	2353
16273295	701	706	MMP-1	Gene	4312
16273295	711	716	MMP-2	Gene	4313
16273295	839	844	MMP-1	Gene	4312
16273295	853	858	MMP-2	Gene	4313
16273295	897	906	IL-1alpha	Gene	3552
16273295	911	919	IL-1beta	Gene	3553
16273295	929	934	MMP-1	Gene	4312
16273295	943	948	MMP-2	Gene	4313
16273295	996	1005	IL-1alpha	Gene	3552
16273295	1010	1018	IL-1beta	Gene	3553
16273295	1029	1039	MAP kinase	Gene	-1
16273295	1065	1070	c-Jun	Gene	3725
16273295	1075	1080	c-Fos	Gene	2353
16273295	1188	1193	MMP-1	Gene	4312
16273295	1283	1289	IL-1Ra	Gene	3557
16273295	1379	1384	MMP-1	Gene	4312
16273295	1431	1437	IL-1Ra	Gene	3557
16273295	1465	1470	MMP-1	Gene	4312
16273295	1483	1489	IL-1Ra	Gene	3557
16273295	1517	1522	c-Jun	Gene	3725
16273295	1584	1589	c-Fos	Gene	2353
16273295	1676	1681	MMP-1	Gene	4312
16273295	1751	1757	IL-1Ra	Gene	3557
16273295	1766	1771	MMP-1	Gene	4312
16273295	1802	1807	c-Jun	Gene	3725
16273295	1861	1865	IL-1	Gene	3553
16273295	1984	1990	IL-1Ra	Gene	3557

16319131|t|Temporal and parental-specific expression of imprinted genes in a newly derived Chinese human embryonic stem cell line and embryoid bodies.
16319131|a|Although the study of imprinted genes in human development is very important, little is known about their expression and regulation in the early differentiation of human tissues due to lack of an appropriate model. In this study, a Chinese human embryonic stem (hES) cell line, SHhES1, was derived and fully characterized. Expression profiles of human imprinted genes were determined by Affymetrix Oligo micro-array in undifferentiated SHhES1 cells and SHhES1-derived embryoid bodies (EBs) at day 3, 8, 13 and 18. Thirty-two known human imprinted genes were detected in undifferentiated ES cells. Significantly, differential expression was found in nine genes at different stages of EB formation. Expression profile changes were confirmed by quantitative real-time reverse transcriptase-polymerase chain reaction in SHhES1 cells as well as in another independently derived hES cell line, HUES-7. In addition, the monoallelic expressions of four imprinted genes were examined in three different passages of undifferentiated ES cells and EBs of both hES cell lines. The monoallelic expressions of imprinted genes, H19, PEG10, NDNL1 and KCNQ1 were maintained in both undifferentiated hES cells and derived EBs. More importantly, with the availability of maternal peripheral blood lymphocyte sample, we demonstrated that the maternal expression of KCNQ1 and the paternal expression of NDNL1 and PEG10 were maintained in SHhES1 cells. These data provide the first demonstration that the parental-specific expression of imprinted genes is stable in EBs after extensive differentiation, also indicating that in vitro fertilization protocol does not disrupt the parental monoallelic expression of the imprinted genes examined.
16319131	1252	1255	H19	Gene	283120
16319131	1257	1262	PEG10	Gene	23089
16319131	1264	1269	NDNL1	Gene	54551
16319131	1274	1279	KCNQ1	Gene	3784
16319131	1484	1489	KCNQ1	Gene	3784
16319131	1521	1526	NDNL1	Gene	54551
16319131	1531	1536	PEG10	Gene	23089

16339195|t|A comparison of folic acid deficiency-induced genomic instability in lymphocytes of breast cancer patients and normal non-cancer controls from a Chinese population in Yunnan.
16339195|a|We hypothesized that the genomic response to folate deficiency might be different between breast cancer cases and healthy subjects. To test this hypothesis, we performed a comprehensive study on the genotoxic and cytotoxic effects of in vitro folic acid (FA) deficiency on primary human lymphocytes from 19 breast cancer patients and 20 age-matched healthy females from Yunnan, China using the cytokinesis-block micronucleus assay. Lymphocytes from the volunteers were cultured in RPMI1640 medium containing 30, 120 or 240 nM FA for 9 days. The results showed that 30 nM FA was associated with increased frequencies of micronucleated binucleated cell (MNed BNC), nucleoplasmic bridges (NPB), nuclear buds (BUD), apoptosis (APO) and necrosis (NEC) relative to 120 and 240 nM FA (P<0.001) in lymphocytes of case and control groups in vitro, however there were no significant differences between the 120 and 240 nM FA within each sampling group. The case group showed significantly higher frequencies of MNed BNC than control at 120 and 240 nM FA (P<0.05-0.001) but not at 30 nM FA (P=0.052). NEC was significantly higher in breast cancer group than control at all concentrations of FA (P<0.005). FA concentration explained 60, 39, 39, 52 and 71% of the variance of MNed BNC, NPB, BUD, APO and NEC, respectively compared with breast cancer status which only explained 6 and 7% of the variance of MNed BNC and NEC(Two way ANOVA, P<0.0001). Difference of difference analysis showed that breast cancer cases were not abnormally sensitive to the genome-damaging effect of folate deficiency. We concluded that (i) increased concentrations of FA abolished the genome-damaging effect of FA deficiency in lymphocytes of both breast cancer patients and controls to a similar extent and (ii) FA concentration is much more important than breast cancer status in determining genomic instability and cell death.

16391555|t|Evaluating the role of the 620W allele of protein tyrosine phosphatase PTPN22 in Crohn's disease and multiple sclerosis.
16391555|a|The 620W allele of PTPN22 has been associated with susceptibility to several different forms of chronic inflammatory disease, including Type 1 diabetes (T1D), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and autoimmune thyroiditis (AIT). We set out to explore its possible role in two other inflammatory diseases: multiple sclerosis (MS) and Crohn's disease (CD). In our cohort of 496 MS trios from the United Kingdom, we observed reduced transmission of the PTPN22 620W allele. The CD sample consisted of 169 trios as well as 249 cases of CD with their 207 matched control subjects collected in the province of Québec, Canada; there was also no evidence of association between the PTPN22 620W allele and susceptibility for CD. Pooled analyses combining our data with published data assessed a total of 1496 cases of MS and 1019 cases of CD but demonstrated no evidence of association with either disease. Given the modest odds ratios of known risk alleles for inflammatory diseases, these analyses do not exclude a role for the PTPN22 allele in susceptibility to CD or MS, but they do suggest that such a putative role would probably be more modest than that reported so far in T1D, RA, SLE, and AIT.
16391555	42	70	protein tyrosine phosphatase	Gene	26191
16391555	71	77	PTPN22	Gene	26191
16391555	140	146	PTPN22	Gene	26191
16391555	598	604	PTPN22	Gene	26191
16391555	822	828	PTPN22	Gene	26191
16391555	1169	1175	PTPN22	Gene	26191

16412238|t|Peroxisomal proliferator activated receptor-gamma deficiency in a Canadian kindred with familial partial lipodystrophy type 3 (FPLD3).
16412238|a|BACKGROUND: Familial partial lipodystrophy (Dunnigan) type 3 (FPLD3, Mendelian Inheritance in Man [MIM] 604367) results from heterozygous mutations in PPARG encoding peroxisomal proliferator-activated receptor-gamma. Both dominant-negative and haploinsufficiency mechanisms have been suggested for this condition. METHODS: We present a Canadian FPLD3 kindred with an affected mother who had loss of fat on arms and legs, but no increase in facial, neck, suprascapular or abdominal fat. She had profound insulin resistance, diabetes, severe hypertriglyceridemia and relapsing pancreatitis, while her pre-pubescent daughter had normal fat distribution but elevated plasma triglycerides and C-peptide and depressed high-density lipoprotein cholesterol. RESULTS: The mother and daughter were each heterozygous for PPARG nonsense mutation Y355X, whose protein product in vitro was transcriptionally inactive with no dominant-negative activity against the wild-type receptor. In addition the mutant protein appeared to be markedly unstable. CONCLUSION: Taken together with previous studies of human PPARG mutations, these findings suggest that PPAR-gamma deficiency due either to haploinsufficiency or to substantial activity loss due to dominant negative interference of the normal allele product's function can each contribute to the FPLD3 phenotype.
16412238	0	49	Peroxisomal proliferator activated receptor-gamma	Gene	5468
16412238	286	291	PPARG	Gene	5468
16412238	301	350	peroxisomal proliferator-activated receptor-gamma	Gene	5468
16412238	638	645	insulin	Gene	3630
16412238	945	950	PPARG	Gene	5468
16412238	1228	1233	PPARG	Gene	5468
16412238	1273	1283	PPAR-gamma	Gene	5468

16463024|t|The TNFalpha receptor TNFRSF1A and genes encoding the amiloride-sensitive sodium channel ENaC as modulators in cystic fibrosis.
16463024|a|The CFTR mutations in cystic fibrosis (CF) lead to ion transport anomalities which predispose to chronic infection and inflammation of CF airways as the major determinants for morbidity and mortality in CF. Discordant clinical phenotypes of siblings with identical CFTR mutations and the large variability of clinical manifestations of patients who are homozygous for the most common mutation F508del suggest that both environment and genes other than CFTR contribute substantially to CF disease. The prime candidates for genetic modifiers in CF are elements of host defence such as the TNFalpha receptor and of ion transport such as the amiloride-sensitive epithelial sodium channel ENaC, both of which are encoded side by side on 12p13 (TNFRSF1A, SCNN1A) and 16p12 (SCNN1B, SCNN1G). Thirty-seven families with F508del-CFTR homozygous siblings exhibiting extreme clinical phenotypes that had been selected from the 467 pairs of the European CF Twin and Sibling Study were genotyped at 12p13 and 16p12 markers. The ENaC was identified as a modulator of CF by transmission disequilibrium at SCNN1G and association with CF phenotype intrapair discordance at SCNN1B. Family-based and case-control analyses and sequencing of SCNN1A and TNFRSF1A uncovered an association of the TNFRSF1A intron 1 haplotype with disease severity. Carriers of risk haplotypes were underrepresented suggesting a strong impact of both loci on survival. The finding that TNFRSF1A, SCNN1B and SCNN1G are clinically relevant modulators of CF disease supports current concepts that the depletion of airway surface liquid and inadequate host inflammatory responses trigger pulmonary disease in CF.
16463024	22	30	TNFRSF1A	Gene	7132
16463024	132	136	CFTR	Gene	1080
16463024	393	397	CFTR	Gene	1080
16463024	580	584	CFTR	Gene	1080
16463024	867	875	TNFRSF1A	Gene	7132
16463024	877	883	SCNN1A	Gene	6337
16463024	896	902	SCNN1B	Gene	6338
16463024	904	910	SCNN1G	Gene	6340
16463024	948	952	CFTR	Gene	1080
16463024	1218	1224	SCNN1G	Gene	6340
16463024	1284	1290	SCNN1B	Gene	6338
16463024	1349	1355	SCNN1A	Gene	6337
16463024	1360	1368	TNFRSF1A	Gene	7132
16463024	1401	1409	TNFRSF1A	Gene	7132
16463024	1572	1580	TNFRSF1A	Gene	7132
16463024	1582	1588	SCNN1B	Gene	6338
16463024	1593	1599	SCNN1G	Gene	6340

16510324|t|Chiari type I malformation in four unrelated patients affected with Fabry disease.
16510324|a|Fabry disease (FD) is an X-linked inborn error of metabolism resulting from the deficient activity of alpha-galactosidase A which leads to the widespread deposition of glycosphingolipids in lysosomes, and to ischemic complications involving kidneys, heart and brain. Among neurological symptoms, strokes and transient ischemic attacks (TIA) have been reported. A 30-year-old male patient, with FD, was referred to us for evaluation of a sudden episode of dizziness, with disequilibrium, and diplopia, in agreement with the diagnosis of a TIA. Head magnetic resonance imaging (MRI) showed no cerebrovascular involvement but revealed the presence of Chiari type I malformation (CMI). We subsequently performed head MRI in a cohort of 44 consecutive hemizygous male patients and seven heterozygous females affected with FD, and identified three additional cases (two males and one female) of CMI. Whether the association is coincidental or not will need further studies but our data suggest that CMI should be ruled out in all Fabry patients.
16510324	185	206	alpha-galactosidase A	Gene	2717

16525709|t|Fibrin sealant promotes migration and proliferation of human articular chondrocytes: possible involvement of thrombin and protease-activated receptors.
16525709|a|Fibrin sealant (FS), a biological adhesive material, has been recently recommended as an adjunct in autologous chondrocyte implantation (ACI). While FS has been shown to possess osteoinductive potential, little is known about its effects on chondrogenic cells. In this study, we assessed the bioactivity of FS (Tisseel) on the migration and proliferation of human articular chondrocytes in vitro. Using a co-culture assay to mimic matrix-induced ACI (MACI), chondrocytes were found to migrate from collagen membranes towards FS within 12 h of culture, with significant migratory activity evident by 24 h. In addition, 5-bromo-2'-deoxyuridine (BrdU) incorporation experiments revealed that thrombin, the active component of the tissue glue, stimulated chondrocyte proliferation, with maximal efficacy observed at 48 h post-stimulation (1-10 U/ml). In an effort to elucidate the molecular mechanisms underlying these thrombin-induced effects, we examined the expression and activation of protease-activated receptors (PARs), established thrombin receptors. Using a combination of RT-PCR and immunohistochemistry, all four PARs were detected in human chondrocytes, with PAR-1 being the major isoform expressed. Moreover, thrombin and a PAR-1, but not other PAR-isotype-specific peptide agonists, were found to induce rapid intracellular Ca2+ responses in human chondrocytes in calcium mobilization assays. Together, these data demonstrate that FS supports both the migration and proliferation of human chondrocytes. We propose that these effects are mediated, at least in part, via thrombin-induced PAR-1 signalling in human chondrocytes.
16525709	109	117	thrombin	Gene	2147
16525709	841	849	thrombin	Gene	2147
16525709	1067	1075	thrombin	Gene	2147
16525709	1319	1324	PAR-1	Gene	2149
16525709	1370	1378	thrombin	Gene	2147
16525709	1385	1390	PAR-1	Gene	2149
16525709	1731	1739	thrombin	Gene	2147
16525709	1748	1753	PAR-1	Gene	2149

16525711|t|WISP-2 expression in human salivary gland tumors.
16525711|a|This study was designed to disclose detailed genetic mechanisms in salivary gland tumors (SGTs) for development of novel independent marker. We constructed an in-house cDNA microarray carrying 2,201 cDNA clones derived from SGT and oral squamous cell carcinoma cDNA libraries. Four cell lines that originated from the SGT-derived cell lines were analyzed using this microarray system. The genes identified by our microarray system were further analyzed at the mRNA or protein expression level in other types of human cancer cell lines and clinical samples (ten normal salivary glands [NSGs], eleven pleomorphic adenomas, ten adenoid cystic carcinomas and three adenocarcinomas). Two up-regulated genes and six down-regulated genes were identified in common when compared with the control RNA. Of the up-regulated genes, WISP-2, which plays an important role in breast carcinogenesis, was selected for further analyses. We found a higher expression of the WISP-2 gene in the SGT-derived cell lines compared with other types of human cancer cell lines. Furthermore, WISP-2 mRNA and protein expression levels in NSGs were significantly higher than those in SGTs. These results suggest that WISP-2 could be a reliable independent marker and that down-regulation or loss of the WISP-2 gene may be associated with the development of SGTs.
16525711	0	6	WISP-2	Gene	8839
16525711	870	876	WISP-2	Gene	8839
16525711	1005	1011	WISP-2	Gene	8839
16525711	1114	1120	WISP-2	Gene	8839
16525711	1237	1243	WISP-2	Gene	8839
16525711	1323	1329	WISP-2	Gene	8839

16526029|t|Evaluation of RGS4 as a candidate gene for schizophrenia.
16526029|a|Several studies have suggested that the regulator of G-protein signaling 4 (RGS4) may be a positional and functional candidate gene for schizophrenia. Three single nucleotide polymorphisms (SNP) located at the promoter region (SNP4 and SNP7) and the intron 1 (SNP18) of RGS4 have been verified in different ethnic groups. Positive results have been reported in these SNPs with different numbers of SNP combinatory haplotypes. In this study, these three SNP markers were genotyped in 218 schizophrenia pedigrees of Taiwan (864 individuals) for association analysis. Among these three SNPs, neither SNP4, SNP7, SNP18 has shown significant association with schizophrenia in single locus association analysis, nor any compositions of the three SNP haplotypes has shown significantly associations with the DSM-IV diagnosed schizophrenia. Our results fail to support the RGS4 as a candidate gene for schizophrenia when evaluated from these three SNP markers.
16526029	14	18	RGS4	Gene	5999
16526029	98	132	regulator of G-protein signaling 4	Gene	5999
16526029	134	138	RGS4	Gene	5999
16526029	328	332	RGS4	Gene	5999
16526029	923	927	RGS4	Gene	5999

16541406|t|Distinct patterns of germ-line deletions in MLH1 and MSH2: the implication of Alu repetitive element in the genetic etiology of Lynch syndrome (HNPCC).
16541406|a|A relatively high frequency of germ-line genomic rearrangements in MLH1 and MSH2 has been reported among Lynch Syndrome (HNPCC) patients from different ethnic populations. To investigate the underlying molecular mechanisms, we characterized the DNA breakpoints of 11 germ-line deletions, six for MLH1 and five for MSH2. Distinct deletion patterns were found for the two genes. The five cases of MSH2 deletions result exclusively from intragenic unequal recombination mediated by repetitive Alu sequences. In contrast, five out of the six MLH1 deletions are due to recombinations involving sequences of no significant homology (P=0.015). A detailed analysis of the DNA breakpoints in the two genes, previously characterized by other groups, validated the observation that Alu-mediated unequal recombination is the main type of deletion in MSH2 (n=34), but not in MLH1 (n=21) (P<0.0001). Plotting the distribution of known DNA breakpoints among the introns of the two genes showed that, the highest breakpoint density is co-localized with the highest Alu density. Our study suggests that Alu is a promoting factor for the genomic recombinations in both MLH1 and MSH2, and the local Alu density may be involved in shaping the deletion pattern.
16541406	44	48	MLH1	Gene	4292
16541406	53	57	MSH2	Gene	4436
16541406	219	223	MLH1	Gene	4292
16541406	228	232	MSH2	Gene	4436
16541406	448	452	MLH1	Gene	4292
16541406	466	470	MSH2	Gene	4436
16541406	547	551	MSH2	Gene	4436
16541406	690	694	MLH1	Gene	4292
16541406	990	994	MSH2	Gene	4436
16541406	1014	1018	MLH1	Gene	4292
16541406	1303	1307	MLH1	Gene	4292
16541406	1312	1316	MSH2	Gene	4436

16611040|t|Gene therapy for cystic fibrosis airway disease- is clinical success imminent?
16611040|a|Cystic fibrosis (CF) was one of the first inherited disorders for which gene therapy was seriously considered as a realistic option for treatment, and as such, it has long provided a paradigm for gene therapy of inherited diseases. However, despite the cloning of the cystic fibrosis transmembrane conductance regulator gene in 1989, over 15 years later a practical gene therapy for CF has not eventuated. There are a number of reasons for this, and analysis of the specific issues that have delayed the successful development of gene therapy for CF also provides general insights into the practical complexities involved in the development of gene therapy for inherited disorders. The issues which have prevented the application of gene therapy for CF to date include the lack of suitable gene delivery technologies, the complexities of the interactions between the host and vector, the biology of the lung airways, and the nature of the pathology found in individuals with CF. We will discuss the history of CF gene therapy with specific reference to these and other issues that pre-occupy the field at present: namely, the question of what vectors appear to be suitable for airway gene delivery in CF, what cells must be targeted, how airway epithelium defences can be overcome or eluded to allow efficient gene delivery, how to ensure safe and long-term transgene expression and the need to identify relevant surrogate success measures that can be used to assess the outcome of gene therapy in CF patients.
16611040	347	398	cystic fibrosis transmembrane conductance regulator	Gene	1080

16648377|t|Mutations responsible for Larsen syndrome cluster in the FLNB protein.
16648377|a|BACKGROUND: A gene for Larsen syndrome was recently described, and mutations were reported in five cases. OBJECTIVE: To test whether mutations in this gene, FLNB, could explain the disease in our independent collection of sporadic and dominant Larsen syndrome cases; and to test whether mutations occurred in a non-random pattern. RESULTS: Missense mutations were found in each of five cases. Four of the five were new; one was reported in a sporadic case in the original Larsen syndrome study of five cases. All mutations from the two studies were compiled. Clustered mutations were observed within three filamin B protein domains: the calponin homology 2 domain, repeat 14, and repeat 15. This suggested that as few as five (of the total of 46) coding exons of FLNB could be screened to detect Larsen syndrome mutations. Four of these exons were screened in a sixth (sporadic) case and a previously reported G1691S substitution mutation detected. CONCLUSIONS: Mutations in FLNB may be responsible for all cases of Larsen syndrome. They appear to occur in specific functional domains of the filamin B protein. This should simplify diagnostic screening of the FLNB gene. Analyses in larger patient series are warranted to quantify this. The study confirmed the extreme variability in clinical presentation and the presence of unaffected carriers. A molecular screen would be valuable for diagnosis and genetic counselling.
16648377	57	61	FLNB	Gene	2317
16648377	228	232	FLNB	Gene	2317
16648377	677	686	filamin B	Gene	2317
16648377	834	838	FLNB	Gene	2317
16648377	1046	1050	FLNB	Gene	2317
16648377	1163	1172	filamin B	Gene	2317
16648377	1231	1235	FLNB	Gene	2317

16688748|t|Array-based comparative genomic hybridization facilitates identification of breakpoints of a novel der(1)t(1;18)(p36.3;q23)dn in a child presenting with mental retardation.
16688748|a|Monosomy of distal 1p36 represents the most common terminal deletion in humans and results in one of the most frequently diagnosed mental retardation syndromes. This deletion is considered a contiguous gene deletion syndrome, and has been shown to vary in deletion sizes that contribute to the spectrum of phenotypic anomalies seen in patients with monosomy 1p36. We report on an 8-year-old female with characteristics of the monosomy 1p36 syndrome who demonstrated a novel der(1)t(1;18)(p36.3;q23). Initial G-banded karyotype analysis revealed a deleted chromosome 1, with a breakpoint within 1p36.3. Subsequent FISH and array-based comparative genomic hybridization not only confirmed and partially characterized the deletion of chromosome 1p36.3, but also uncovered distal trisomy for 18q23. In this patient, the duplicated 18q23 is translocated onto the deleted 1p36.3 region, suggesting telomere capture. Molecular characterization of this novel der(1)t(1;18)(p36.3;q23), guided by our clinical array-comparative genomic hybridization, demonstrated a 3.2 Mb terminal deletion of chromosome 1p36.3 and a 200 kb duplication of 18q23 onto the deleted 1p36.3, presumably stabilizing the deleted chromosome 1. DNA sequence analysis around the breakpoints demonstrated no homology, and therefore this telomere capture of distal 18q is apparently the result of a non-homologous recombination. Partial trisomy for 18q23 has not been previously reported. The importance of mapping the breakpoints of all balanced and unbalanced translocations found in the clinical laboratory, when phenotypic abnormalities are found, is discussed.

16691587|t|Clinical and molecular characterization of individuals with 18p deletion: a genotype-phenotype correlation.
16691587|a|The deletion 18p syndrome is one of the most common chromosome abnormalities. The medical problems are mental and postnatal growth retardation, and sometimes malformations of the heart and brain. The individuals have some typical features, which might be easy to overlook and which are: ptosis, strabismus, hypertelorism, broad flat nose, micrognathia, big and low set ears. The aims of present study were to clinically and molecularly characterize the syndrome further in seven subjects with de novo 18p deletions and to perform genotype-phenotype correlation. All seven subjects had terminal deletions and no interstitial deletion was observed with subtelomeric FISH analyses. To define the extent of the 18p deletions and the parental origin of the deletion microsatellite- and FISH analyses were performed on genomic DNA and on lymphoblastoid cell lines of the study participants. Totally 19 chromosomes, 18 specific polymorphic microsatellite markers, and 5 BAC clones were used. The results revealed that the deletions were located in the centromeric region at 18p11.1 in four of the seven subjects. In the remaining three the breakpoints were located distal to 18p11.1 (18p11.21-p11.22). Four of the individuals had a paternal and three a maternal origin of the deletion. Genotype-phenotype correlation of the seven subjects suggests a correlation between the extent of the deleted region and the mental development. All the four children with a deletion in the centromeric region at 18p11.1 had a mental retardation (MR). Two of the three children with a more distal breakpoint (distal 18p11.21) had a normal mental development and one had a border-line mental retardation. There might be a critical region for the mental retardation located between 18p11.1 and 18p11.21. The children with a breakpoint at 18p11.1 had all a broad face, which was observed in only one of those with a more distal breakpoint, otherwise no genotype-phenotype correlation of the features was observed.

16691619|t|Split-hand/split-foot malformation 3 (SHFM3) at 10q24, development of rapid diagnostic methods and gene expression from the region.
16691619|a|Split-hand/split-foot malformation (SHFM, also called ectrodactyly) is a clinically variable and genetically heterogeneous group of limb malformations. Several SHFM loci have been mapped, including SHFM1 (7q21), SHFM2 (Xq26), SHFM3 (10q24), SHFM4 (3q27) and SHFM5 (2q31). To date, mutations in a gene (TP63) have only been identified for SHFM4. SHFM3 has been shown by pulsed-field gel electrophoresis to be caused by an approximately 500 kb DNA rearrangement at 10q24. This region contains a number of candidate genes for SHFM3, though which gene(s) is (are) involved in the pathogenesis of SHFM3 is not known. Our aim in this study was to improve the diagnosis of SHFM3, and to begin to understand which genes are involved in SHFM3. Here we show, using two different techniques, FISH and quantitative PCR that SHFM3 is caused by a minimal 325 kb duplication containing only two genes (BTRC and POLL). The data presented provide improved methods for diagnosis and begin to elucidate the pathogenic mechanism of SHFM3. Expression analysis of 13 candidate genes within and flanking the duplicated region shows that BTRC (present in three copies) and SUFU (present in two copies) are overexpressed in SHFM3 patients compared to controls. Our data suggest that SHFM3 may be caused by overexpression of BTRC and SUFU, both of which are involved in beta-catenin signalling.
16691619	11	36	split-foot malformation 3	Gene	100049542
16691619	330	335	SHFM1	Gene	7979
16691619	344	349	SHFM2	Gene	6463
16691619	373	378	SHFM4	Gene	8626
16691619	390	395	SHFM5	Gene	171157
16691619	434	438	TP63	Gene	8626
16691619	470	475	SHFM4	Gene	8626
16691619	1019	1023	BTRC	Gene	8945
16691619	1028	1032	POLL	Gene	27343
16691619	1246	1250	BTRC	Gene	8945
16691619	1281	1285	SUFU	Gene	51684
16691619	1431	1435	BTRC	Gene	8945
16691619	1440	1444	SUFU	Gene	51684

16737910|t|Identification of the nuclear localization motif in the ETV6 (TEL) protein.
16737910|a|ETV6, or Translocation-Ets-Leukemia (TEL), is an ETS family transcriptional repressor that is essential for establishing hematopoiesis in neonatal bone marrow, and is frequently a target of chromosomal translocations in human cancer. ETV6 is predominantly a nuclear phosphoprotein that represses transcription by binding directly to the promoters of target genes. The nuclear localization mechanism of ETV6, however, is not well understood. In this report, we provide evidence that a nuclear localization signal (NLS) exists in the C-terminal region of ETV6. ETV6 proteins with mutations outside of amino acids 332-452 localize to the nucleus, whereas proteins with mutations within amino acids 332-452 remain in the cytoplasm. Furthermore, when a fragment of ETV6 comprised of amino acids 332-452 was fused to cytoplasmic beta-galactosidase protein, the fusion protein was able to enter the nucleus. These results strongly indicate that residues 332-452 mediate nuclear localization of ETV6.
16737910	56	60	ETV6	Gene	2120
16737910	62	65	TEL	Gene	2120
16737910	76	80	ETV6	Gene	2120
16737910	85	111	Translocation-Ets-Leukemia	Gene	2120
16737910	113	116	TEL	Gene	2120
16737910	310	314	ETV6	Gene	2120
16737910	478	482	ETV6	Gene	2120
16737910	629	633	ETV6	Gene	2120
16737910	635	639	ETV6	Gene	2120
16737910	836	840	ETV6	Gene	2120
16737910	899	917	beta-galactosidase	Gene	2720
16737910	1063	1067	ETV6	Gene	2120

16786513|t|McArdle disease: the mutation spectrum of PYGM in a large Italian cohort.
16786513|a|Deficiency of the muscle isozyme of glycogen phosphorylase is causative of McArdle disease or Glycogen storage disease type V (GSD-V), the most common autosomal recessive disorder of glycogen metabolism. The typical clinical presentation is characterized by exercise intolerance with cramps, and recurrent myoglobinuria. To date, 46 mutations in the PYGM gene have been detected in GSD-V patients. We report the mutational spectrum in 68 Italian patients. We identified 30 different mutations in the PYGM gene, including 19 mutations that have not been reported previously. The novel mutations include: eight missense mutations (c.475G>A, p.G159R; c.689C>G, p.P230R; c.1094C>T, p.A365E; c.1151C>A, p.A384D; c.1182C>T, p.R428C; c.1471C>T, p.R491C; c.2444A>C, p.D815A; c.2477G>C, p.W826S), two nonsense mutations (c.1475G>A, p.W492X; c.1627A>T, p.K543X), five splice site mutations (c.855 +1G>C; c.1092 +1G>A; c. 1093-1G>T; c.1239 +1G>A; c.2380 +1G>A), and four deletions (c.715_717delGTC, p.V239del; c.304delA, p.N102DfsX4; c.1970_2177del, p.V657_G726; c.2113_2114delGG, p.G705RfsX16). Whereas we confirmed lack of direct correlation between the clinical phenotype and the genotype, we also found that the so-called 'common mutation' (p.R50X) accounted for about 43% of alleles in our cohort and that no population-related mutations are clearly identified in Italian patients.
16786513	42	46	PYGM	Gene	5837
16786513	424	428	PYGM	Gene	5837
16786513	574	578	PYGM	Gene	5837

17006606|t|A polymorphism of C-to-T substitution at -31 IL1B is associated with the risk of advanced gastric adenocarcinoma in a Japanese population.
17006606|a|Proinflammatory cytokine gene polymorphisms have been demonstrated to associate with gastric cancer risk, of which IL1B-31T/C and -511C/T changes have been well investigated due to the possibility that they may alter the IL1B transcription. The signal transduction target upon interleukin 1 beta (IL1beta) stimulation, the nuclear factor of kappa B (NFkappaB) activation, supports cancer development, signal transduction in which is mediated by FS-7 cell-associated cell surface antigen (FAS) signaling. Based on recent papers describing the prognostic roles of the polymorphisms and the NFkappaB functions on cancer development, we sought to determine if Japanese gastric cancer patients were affected by the IL1B -31/-511 and FAS-670 polymorphisms. A case-control study was conducted on incident gastric adenocarcinoma patients (n=271) and age-gender frequency-matched control subjects (n=271). We observed strong linkage disequilibrium between the T allele at -511 and the C allele at -31 and between the C allele at -511 and the T allele at -31 in IL1B in both the cases and controls (R (2)=0.94). Neither IL1B-31, -511 nor FAS-670 polymorphisms showed significantly different risks of gastric adenocarcinoma. Though FAS-670 polymorphisms did not show any significant difference, the proportion of subjects with IL1B-31TT (or IL1B-511CC) increased according to stage (trend P=0.019). In particular, subjects with stage IV had a two times higher probability of having either IL1B-31TT (or IL1B-511CC) genotype compared with stage I subjects. These observations suggest that IL1B-31TT and IL1B-511CC are associated with disease progression.
17006606	45	49	IL1B	Gene	3553
17006606	254	258	IL1B	Gene	3553
17006606	360	364	IL1B	Gene	3553
17006606	416	434	interleukin 1 beta	Gene	3553
17006606	436	443	IL1beta	Gene	3553
17006606	462	487	nuclear factor of kappa B	Gene	4790
17006606	489	497	NFkappaB	Gene	4790
17006606	584	625	FS-7 cell-associated cell surface antigen	Gene	355
17006606	627	630	FAS	Gene	355
17006606	727	735	NFkappaB	Gene	4790
17006606	849	853	IL1B	Gene	3553
17006606	867	870	FAS	Gene	355
17006606	1191	1195	IL1B	Gene	3553
17006606	1249	1253	IL1B	Gene	3553
17006606	1267	1270	FAS	Gene	355
17006606	1360	1363	FAS	Gene	355
17006606	1455	1459	IL1B	Gene	3553
17006606	1469	1473	IL1B	Gene	3553
17006606	1617	1621	IL1B	Gene	3553
17006606	1631	1635	IL1B	Gene	3553
17006606	1716	1720	IL1B	Gene	3553
17006606	1730	1734	IL1B	Gene	3553

17033686|t|A two base pair deletion in the PQBP1 gene is associated with microphthalmia, microcephaly, and mental retardation.
17033686|a|X-linked mental retardation has been traditionally divided into syndromic (S-XLMR) and non-syndromic forms (NS-XLMR), although the borderlines between these phenotypes begin to vanish and mutations in a single gene, for example PQBP1, can cause S-XLMR as well as NS-XLMR. Here, we report two maternal cousins with an apparently X-linked phenotype of mental retardation (MR), microphthalmia, choroid coloboma, microcephaly, renal hypoplasia, and spastic paraplegia. By multipoint linkage analysis with markers spanning the entire X-chromosome we mapped the disease locus to a 28-Mb interval between Xp11.4 and Xq12, including the BCOR gene. A missense mutation in BCOR was described in a family with Lenz microphthalmia syndrome, a phenotype showing substantial overlapping features with that described in the two cousins. However, no mutation in the BCOR gene was found in both patients. Subsequent mutation analysis of PQBP1, located within the delineated linkage interval in Xp11.23, revealed a 2-bp deletion, c.461_462delAG, that cosegregated with the disease. Notably, the same mutation is associated with the Hamel cerebropalatocardiac syndrome, another form of S-XLMR. Haplotype analysis suggests a germline mosaicism of the 2-bp deletion in the maternal grandmother of both affected individuals. In summary, our findings demonstrate for the first time that mutations in PQBP1 are associated with an S-XLMR phenotype including microphthalmia, thereby further extending the clinical spectrum of phenotypes associated with PQBP1 mutations.
17033686	32	37	PQBP1	Gene	10084
17033686	344	349	PQBP1	Gene	10084
17033686	745	749	BCOR	Gene	54880
17033686	779	783	BCOR	Gene	54880
17033686	966	970	BCOR	Gene	54880
17033686	1036	1041	PQBP1	Gene	10084
17033686	1493	1498	PQBP1	Gene	10084
17033686	1643	1648	PQBP1	Gene	10084

17036344|t|A case surviving for over a year of renal tubular dysgenesis with compound heterozygous angiotensinogen gene mutations.
17036344|a|Renal tubular dysgenesis (RTD) is a developmental abnormality of the renal proximal tubules found in patients with Potter syndrome. We report a female newborn with RTD who has survived for more than 18 months. Infusions of fresh frozen plasma (FFP) in the early neonatal period were effective in raising and maintaining her blood pressure. Peritoneal dialysis was required until the appearance of spontaneous urination at 29 days after birth. Histopathological examinations of the kidney revealed dilated renal tubular lumina and foamy columnar epithelial cells in the renal tubules. Endocrinological studies showed a discrepancy between low plasma renin activity (<0.1 ng/ml/hr) and high active renin concentration (135,000 pg/ml), suggesting an aberration in the renin substrate, angiotensinogen. Direct sequencing analysis revealed two novel mutations in the coding region of the angiotensinogen gene (AGT): a nonsense mutation in exon 2 (c.604C > T) and a frameshift deletion at nucleotide 1290 in exon 5 (c.1290delT). The mutations were in the compound heterozygous state, because each parent had each mutation. These findings suggest that angiotensinogen deficiency is one of the causes of RTD. A treatment of the condition with FFP may help to promote long survival.
17036344	88	103	angiotensinogen	Gene	183
17036344	769	774	renin	Gene	5972
17036344	816	821	renin	Gene	5972
17036344	885	890	renin	Gene	5972
17036344	902	917	angiotensinogen	Gene	183
17036344	1003	1018	angiotensinogen	Gene	183
17036344	1025	1028	AGT	Gene	183
17036344	1265	1280	angiotensinogen	Gene	183

17160890|t|Functional variants in the promoter region of Chitinase 3-like 1 (CHI3L1) and susceptibility to schizophrenia.
17160890|a|The chitinase 3-like 1 gene (CHI3L1) is abnormally expressed in the hippocampus of subjects with schizophrenia and may be involved in the cellular response to various environmental events that are reported to increase the risk of schizophrenia. Here, we provide evidence that the functional variants at the CHI3L1 locus influence the genetic risk of schizophrenia. First, using case-control and transmission/disequilibrium-test (TDT) methodologies, we detected a significant association between schizophrenia and haplotypes within the promoter region of CHI3L1 in two independent cohorts of Chinese individuals. Second, the at-risk CCC haplotype (P=.00058 and .0018 in case-control and TDT studies, respectively) revealed lower transcriptional activity (P=2.2 x 10(-7)) and was associated with lower expression (P=3.1 x 10(-5)) compared with neutral and protective haplotypes. Third, we found that an allele of SNP4 (rs4950928), the tagging SNP of CCC, impaired the MYC/MAX-regulated transcriptional activation of CHI3L1 by altering the transcriptional-factor consensus sequences, and this may be responsible for the decreased expression of the CCC haplotype. In contrast, the protective TTG haplotype was associated with a high level of CHI3L1 expression. Our findings identify CHI3L1 as a potential schizophrenia-susceptibility gene and suggest that the genes involved in the biological response to adverse environmental conditions are likely to play roles in the predisposition to schizophrenia.
17160890	46	64	Chitinase 3-like 1	Gene	1116
17160890	66	72	CHI3L1	Gene	1116
17160890	115	133	chitinase 3-like 1	Gene	1116
17160890	140	146	CHI3L1	Gene	1116
17160890	418	424	CHI3L1	Gene	1116
17160890	665	671	CHI3L1	Gene	1116
17160890	1077	1080	MYC	Gene	4609
17160890	1081	1084	MAX	Gene	4149
17160890	1125	1131	CHI3L1	Gene	1116
17160890	1349	1355	CHI3L1	Gene	1116
17160890	1390	1396	CHI3L1	Gene	1116

17160896|t|Orofacial cleft risk is increased with maternal smoking and specific detoxification-gene variants.
17160896|a|Maternal smoking is a recognized risk factor for orofacial clefts. Maternal or fetal pharmacogenetic variants are plausible modulators of this risk. In this work, we studied 5,427 DNA samples, including 1,244 from subjects in Denmark and Iowa with facial clefting and 4,183 from parents, siblings, or unrelated population controls. We examined 25 single-nucleotide polymorphisms in 16 genes in pathways for detoxification of components of cigarette smoke, to look for evidence of gene-environment interactions. For genes identified as related to oral clefting, we studied gene-expression profiles in fetal development in the relevant tissues and time intervals. Maternal smoking was a significant risk factor for clefting and showed dosage effects, in both the Danish and Iowan data. Suggestive effects of variants in the fetal NAT2 and CYP1A1 genes were observed in both the Iowan and the Danish participants. In an expanded case set, NAT2 continued to show significant overtransmission of an allele to the fetus, with a final P value of .00003. There was an interaction between maternal smoking and fetal inheritance of a GSTT1-null deletion, seen in both the Danish (P=.03) and Iowan (P=.002) studies, with a Fisher's combined P value of <.001, which remained significant after correction for multiple comparisons. Gene-expression analysis demonstrated expression of GSTT1 in human embryonic craniofacial tissues during the relevant developmental interval. This study benefited from two large samples, involving independent populations, that provided substantial power and a framework for future studies that could identify a susceptible population for preventive health care.
17160896	927	931	NAT2	Gene	10
17160896	936	942	CYP1A1	Gene	1543
17160896	1035	1039	NAT2	Gene	10
17160896	1223	1228	GSTT1	Gene	2952
17160896	1469	1474	GSTT1	Gene	2952

17185386|t|Families with the risk allele of DISC1 reveal a link between schizophrenia and another component of the same molecular pathway, NDE1.
17185386|a|We have previously reported a robust association between an allelic haplotype of 'Disrupted in Schizophrenia 1' (DISC1) and schizophrenia in a nationwide collection of Finnish schizophrenia families. This specific DISC1 allele was later identified to associate with visual working memory, selectively in males. DISC1 association to schizophrenia has since been replicated in multiple independent study samples from different populations. In this study, we conditioned our sample of Finnish families for the presence of the Finnish tentative risk allele for DISC1 and re-analyzed our genome-wide scan data of 443 markers on the basis of this stratification. Two additional loci displayed an evidence of linkage (LOD > 3) and included a locus on 16p13, proximal to the gene encoding NDE1, which has been shown to biologically interact with DISC1. Although none of the observed linkages remained significant after multiple test correction through simulation, further analysis of NDE1 revealed an association between a tag-haplotype and schizophrenia (P = 0.00046) specific to females, which proved to be significant (P = 0.011) after multiple test correction. Our finding would support the concept that initial gene findings in multifactorial diseases will assist in the identification of other components of complex genetic etiology. Notably, this and other converging lines of evidence underline the importance of DISC1-related functional pathways in the etiology of schizophrenia.
17185386	33	38	DISC1	Gene	27185
17185386	128	132	NDE1	Gene	54820
17185386	216	244	Disrupted in Schizophrenia 1	Gene	27185
17185386	247	252	DISC1	Gene	27185
17185386	348	353	DISC1	Gene	27185
17185386	445	450	DISC1	Gene	27185
17185386	691	696	DISC1	Gene	27185
17185386	915	919	NDE1	Gene	54820
17185386	972	977	DISC1	Gene	27185
17185386	1110	1114	NDE1	Gene	54820
17185386	1547	1552	DISC1	Gene	27185

17221874|t|Townes-Brocks syndrome: twenty novel SALL1 mutations in sporadic and familial cases and refinement of the SALL1 hot spot region.
17221874|a|Townes-Brocks syndrome (TBS) is an autosomal dominant malformation syndrome characterized by renal, anal, ear, and thumb anomalies caused by SALL1 mutations. To date, 36 SALL1 mutations have been described in TBS patients. All but three of those, namely p.R276X, p.S372X, and c.1404dupG, have been found only in single families thereby preventing phenotype-genotype correlations. Here we present 20 novel mutations (12 short deletions, five short duplications, three nonsense mutations) in 20 unrelated families. We delineate the phenotypes and report previously unknown ocular manifestations, i.e. congenital cataracts with unilateral microphthalmia. We show that 46 out of the now 56 SALL1 mutations are located between the coding regions for the glutamine-rich domain mediating SALL protein interactions and 65 bp 3' of the coding region for the first double zinc finger domain, narrowing the SALL1 mutational hotspot region to a stretch of 802 bp within exon 2. Of note, only two SALL1 mutations would result in truncated proteins without the glutamine-rich domain, one of which is reported here. The latter is associated with anal, ear, hand, and renal manifestations, indicating that the glutamine-rich domain is not required for typical TBS.
17221874	37	42	SALL1	Gene	6299
17221874	106	111	SALL1	Gene	6299
17221874	270	275	SALL1	Gene	6299
17221874	299	304	SALL1	Gene	6299
17221874	815	820	SALL1	Gene	6299
17221874	1025	1030	SALL1	Gene	6299
17221874	1113	1118	SALL1	Gene	6299

17223398|t|A 6Mb deletion in band 2q22 due to a complex chromosome rearrangement associated with severe psychomotor retardation, microcephaly and distinctive dysmorphic facial features.
17223398|a|High-resolution analyses of complex chromosome rearrangements (CCR) have demonstrated in individuals with abnormal phenotypes that not all seemingly balanced CCRs based on G-banding are completely balanced at breakpoint level. Here we report on an apparently balanced de novo CCR involving chromosomes 2, 3 and 5 present in a 6-month-old girl. She was referred for genetic evaluation because of severe psychomotor retardation, distinctive dysmorphic features and microcephaly. A 1Mb resolution array-CGH analysis of DNA from the patient revealed a deletion of about 6Mb for chromosome 2. FISH analysis showed that the deletion interval found in band 2q22 mapped at the translocation breakpoint, and that the ZFHX1B gene, which is known to be involved in the Mowat-Wilson syndrome, is located within the deletion interval. To our knowledge this is the first case of a complex chromosomal rearrangement associated with Mowat-Wilson syndrome. Our data illustrate the important role for high-resolution investigation of apparently balanced chromosome rearrangements in patients with unexplained psychomotor retardation and/or other clinical features, and should contribute to our understanding of the mechanisms involved in chromosome rearrangement.
17223398	883	889	ZFHX1B	Gene	9839

17267816|t|Overexpression of DNA polymerase beta results in an increased rate of frameshift mutations during base excision repair.
17267816|a|DNA polymerase beta (Pol beta) is important for the base excision repair (BER) pathway. Overexpression of Pol beta is frequently found in cancer cells and is thought to be associated with tumorigenesis. In this study, we examined BER fidelity in extracts derived from a human lymphoblastoid cell line that over expresses Pol beta compared to normal control cells. Using an in vitro mutagenesis assay, we found an increased rate of frameshift mutations arising during DNA repair in whole-cell extracts derived from the Pol beta-overexpressing cells. We demonstrate that the addition of excess Pol beta to a control cell extract enhances the mutagenic potential of the extract. Furthermore, using cell extracts and purified Pol beta, we demonstrate that the mechanism of frameshift formation involves slippage of Pol beta during the one-nucleotide gap-filling step of BER and that this slippage is fixed by strand-displacement synthesis stimulated by an excess of Pol beta.
17267816	18	37	DNA polymerase beta	Gene	5423
17267816	120	139	DNA polymerase beta	Gene	5423
17267816	141	149	Pol beta	Gene	5423
17267816	226	234	Pol beta	Gene	5423
17267816	441	449	Pol beta	Gene	5423
17267816	638	646	Pol beta	Gene	5423
17267816	712	720	Pol beta	Gene	5423
17267816	842	850	Pol beta	Gene	5423
17267816	931	939	Pol beta	Gene	5423
17267816	1082	1090	Pol beta	Gene	5423

17277899|t|Polymorphic Alu insertions and the genetic structure of Iberian Basques.
17277899|a|Eight Alu sequences (ACE, TPA25, PV92, APO, FXIIIB, D1, A25 and B65) were analyzed in two samples from Navarre and Guipúzcoa provinces (Basque Country, Spain). Alu data for other European, Caucasus and North African populations were compiled from the literature for comparison purposes to assess the genetic relationships of the Basques in a broader geographic context. Results of both MDS plot and AMOVA revealed spatial heterogeneity among these three population clusters clearly defined by geography. On the contrary, no substantial genetic heterogeneity was found between the Basque samples, or between Basques and other Europeans (excluding Caucasus populations). Moreover, the genetic information obtained from Alu data conflicts with hypotheses linking the origin of Basques with populations from North Africa (Berbers) or from the Caucasus region (Georgia). In order to explain the reduced genetic heterogeneity detected by Alu insertions among Basque subpopulations, values of the Wright's F(ST )statistic were estimated for both Alu markers and a set of short tandem repeats (STRs) in terms of two geographical scales: (1) the Basque Country, (2) Europe (including Basques). In the Basque area, estimates of Wahlund's effect for both genetic markers showed no statistical difference between Basque subpopulations. However, when this analysis was performed on a European scale, F(ST) values were significantly higher for Alu insertions than for STR alleles. From these results, we suggest that the spatial heterogeneity of the Basque gene pool identified in previous polymorphism studies is relatively recent and probably caused by a differential process of genetic admixture with non-Basque neighboring populations modulated by the effect of a linguistic barrier to random mating.
17277899	94	97	ACE	Gene	1636
17277899	112	115	APO	Gene	84909
17277899	117	123	FXIIIB	Gene	2165
17277899	129	132	A25	Gene	28936

17304050|t|Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States.
17304050|a|Tuberous sclerosis complex is an autosomal dominant neurocutaneous disorder marked by hamartoma growth in multiple organ systems. We performed mutational analyses on 325 individuals with definite tuberous sclerosis complex diagnostic status. We identified mutations in 72% (199/257) of de novo and 77% (53/68) of familial cases, with 17% of mutations in the TSC1 gene and 50% in the TSC2 gene. There were 4% unclassified variants and 29% with no mutation identified. Genotype/phenotype analyses of all observed tuberous sclerosis complex findings in probands were performed, including several clinical features not analyzed in two previous large studies. We showed that patients with TSC2 mutations have significantly more hypomelanotic macules and learning disability in contrast to those with TSC1 mutations, findings not noted in previous studies. We also observed results consistent with two similar studies suggesting that individuals with mutations in TSC2 have more severe symptoms. On performing meta-analyses of our data and the other two largest studies in the literature, we found significant correlations for several features that individual studies did not have sufficient power to conclude. Male patients showed more frequent neurologic and eye symptoms, renal cysts, and ungual fibromas. Correlating genotypes with phenotypes should facilitate the disease management of tuberous sclerosis complex.
17304050	485	489	TSC1	Gene	7248
17304050	510	514	TSC2	Gene	7249
17304050	811	815	TSC2	Gene	7249
17304050	922	926	TSC1	Gene	7248
17304050	1085	1089	TSC2	Gene	7249

17304550|t|Disruption of a synaptotagmin (SYT14) associated with neurodevelopmental abnormalities.
17304550|a|We report cytogenetic and molecular studies of a de novo, apparently balanced t(1;3)(q32.1;q25.1) identified in a 12-year-old female (designated DGAP128) with cerebral atrophy, macrocephaly seizures, and developmental delay. A combination of fluorescence in situ hybridization (FISH) and Southern blot analysis demonstrated disruption of a synaptotagmin gene (SYT14) at the 1q32 breakpoint. Expression of SYT14 in human brain was confirmed using Northern analysis. Because members of the synaptotagmin family of proteins function as sensors that link changes in calcium levels with a variety of biological processes, including neurotransmission and hormone-responsiveness, SYT14 is an intriguing candidate gene for the abnormal development in this child. This is the first known constitutional rearrangement of SYT14, and further systematic genetic analysis and clinical studies of DGAP128 may offer unique insights into the role of SYT14 in neurodevelopment.
17304550	31	36	SYT14	Gene	255928
17304550	448	453	SYT14	Gene	255928
17304550	493	498	SYT14	Gene	255928
17304550	761	766	SYT14	Gene	255928
17304550	899	904	SYT14	Gene	255928
17304550	1021	1026	SYT14	Gene	255928

17318851|t|Interferon regulatory factor 6 (IRF6) and fibroblast growth factor receptor 1 (FGFR1) contribute to human tooth agenesis.
17318851|a|Phenotypic characteristics expressed in syndromes give clues to the factors involved in the cause of isolated forms of the same defects. We investigated two genes responsible for craniofacial syndromes, FGFR1 and IRF6, in a collection of families with isolated tooth agenesis. Cheek swab samples were obtained for DNA analysis from 116 case/parent trios. Probands had at least one developmentally missing tooth, excluding third molars. In addition, we studied 89 cases and 50 controls from Ohio to replicate any positive findings. Genotyping was performed by kinetic polymerase chain-reaction or TaqMan assays. Linkage disequilibrium analysis and transmission distortion of the marker alleles were performed. The same variants in the IRF6 gene that are associated with isolated orofacial clefts are also associated with human tooth agenesis (rs861019, P = 0.058; rs17015215-V274I, P = 0.0006; rs7802, P = 0.004). Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. The craniofacial phenotypic characteristics of these syndromes include oral clefts and preferential tooth agenesis of incisors and premolars, besides pits on the lower lips. Also it appears that preferential premolar agenesis is associated with FGFR1 (P = 0.014) and IRF6 (P = 0.002) markers. There were statistically significant data suggesting that IRF6 interacts not only with MSX1 (P = 0.001), but also with TGFA (P = 0.03).
17318851	0	30	Interferon regulatory factor 6	Gene	3664
17318851	32	36	IRF6	Gene	3664
17318851	42	77	fibroblast growth factor receptor 1	Gene	2260
17318851	79	84	FGFR1	Gene	2260
17318851	325	330	FGFR1	Gene	2260
17318851	335	339	IRF6	Gene	3664
17318851	689	699	polymerase	Gene	2087
17318851	856	860	IRF6	Gene	3664
17318851	1048	1052	IRF6	Gene	3664
17318851	1353	1358	FGFR1	Gene	2260
17318851	1375	1379	IRF6	Gene	3664
17318851	1459	1463	IRF6	Gene	3664
17318851	1488	1492	MSX1	Gene	4487
17318851	1520	1524	TGFA	Gene	7039

17345627|t|Over-expression of BMP4 and BMP5 in a child with axial skeletal malformations and heterotopic ossification: a new syndrome.
17345627|a|Bone morphogenetic proteins (BMPs) are a highly conserved class of signaling molecules that induce ectopic cartilage and bone formation in vivo. Dysregulated expression of bone morphogenetic protein 4 (BMP4) is found in the cells of patients who have fibrodysplasia ossificans progressiva (FOP), a genetic disorder of axial and appendicular skeletal malformation and progressive heterotopic ossification. Loss of function mutations in the bone morphogenetic protein 5 (bmp5) gene leading to under-expression of BMP5 cause the murine short ear syndrome, characterized by small malformed ears and a broad range of axial skeletal malformations. We found features reminiscent of both the short ear mouse and FOP in a child with malformed external ears, multiple malformations of the axial skeleton, and progressive heterotopic ossification in the neck and back. We examined BMP mRNA expression in transformed lymphocytes by semi-quantitative RT-PCR and protein expression by ELISA assays and immunohistochemistry. Elevated levels of BMP4 and BMP5 mRNA and protein were detected in the patient's cells while levels of BMP2 mRNA were unchanged. Our data suggest that dysregulated expression of BMP4 and BMP5 genes is associated with an array of human axial skeletal abnormalities similar to the short ear mouse and FOP.
17345627	19	23	BMP4	Gene	652
17345627	28	32	BMP5	Gene	653
17345627	296	324	bone morphogenetic protein 4	Gene	652
17345627	326	330	BMP4	Gene	652
17345627	563	591	bone morphogenetic protein 5	Gene	653
17345627	593	597	bmp5	Gene	653
17345627	635	639	BMP5	Gene	653
17345627	1153	1157	BMP4	Gene	652
17345627	1162	1166	BMP5	Gene	653
17345627	1237	1241	BMP2	Gene	650
17345627	1312	1316	BMP4	Gene	652
17345627	1321	1325	BMP5	Gene	653

17503474|t|Cytogenetic and molecular characterization of A2BP1/FOX1 as a candidate gene for autism.
17503474|a|Cytogenetic imbalances are increasingly being realized as causes of autism. Here, we report a de novo translocation between the short arms of chromosomes 15 and 16 in a female with autism, epilepsy, and global developmental delay. FISH analysis identified a cryptic deletion of approximately 160 kb at the boundary of the first exon and first intron of the 1.7 Mb ataxin-2 binding protein-1 (A2BP1) gene, also called FOX1. Quantitative real time PCR (Q-PCR) analysis verified a deletion of exon 1 in the 5' promoter region of the A2BP1 gene. Reverse transcription PCR (qRT-PCR) showed reduced mRNA expression in the individual's lymphocytes, demonstrating the functional consequence of the deletion. A2BP1 codes for a brain-expressed RNA binding or splicing factor. Because of emerging evidence in the role of RNA processing and gene regulation in pervasive developmental disorders, we performed further screening of A2BP1 in additional individuals with autism from the Autism Genetics Resource Exchange (AGRE) collection. Twenty-seven SNPs were genotyped across A2BP1 in 206 parent-child trios and two regions showed association at P < or = 0.008 level. No additional deletions or clear mutations were identified in 88 probands by re-sequencing of all exons and surrounding intronic regions or quantitative PCR (Q-PCR) of exon 1. Although only nominal association was observed, and no obvious causal mutations were identified, these results suggest that A2BP1 may affect susceptibility or cause autism in a subset of patients. Further investigations in a larger sample may provide additional information regarding the involvement of this gene in the autistic phenotype.
17503474	46	51	A2BP1	Gene	54715
17503474	52	56	FOX1	Gene	54715
17503474	453	479	ataxin-2 binding protein-1	Gene	54715
17503474	481	486	A2BP1	Gene	54715
17503474	506	510	FOX1	Gene	54715
17503474	619	624	A2BP1	Gene	54715
17503474	789	794	A2BP1	Gene	54715
17503474	1006	1011	A2BP1	Gene	54715
17503474	1152	1157	A2BP1	Gene	54715
17503474	1544	1549	A2BP1	Gene	54715

17557928|t|The IRF5 polymorphism in type 1 diabetes.
17557928|a|The interferon regulatory factor 5 gene (IRF5) has been shown to play a crucial role in harmful immune responses by induction of proinflammatory cytokines. Functional genetic variants associated with increased IRF5 expression of specific isoforms are associated with systemic lupus erythematosus (SLE) and it is possible that they may also predispose to other autoimmune disorders. We tested the association of two IRF5 SNPs, correlated with IRF5 expression and SLE risk, in 947 nuclear family trios type 1 diabetes (T1D) using the transmission disequilibrium test. Our results suggest that the functional IRF5 variations do not confer an obvious risk for T1D.
17557928	4	8	IRF5	Gene	3663
17557928	46	76	interferon regulatory factor 5	Gene	3663
17557928	83	87	IRF5	Gene	3663
17557928	252	256	IRF5	Gene	3663
17557928	457	461	IRF5	Gene	3663
17557928	484	488	IRF5	Gene	3663
17557928	648	652	IRF5	Gene	3663

17627763|t|Single nucleotide polymorphisms of cytokine genes in the healthy Slovak population.
17627763|a|Cytokines are molecules that control and modulate the activities of numerous target cells via binding to specific receptors. The observed differences in the cytokine production among individuals can be, at least partially, explained by gene polymorphisms. Several cytokine gene polymorphisms have been identified to play a role in susceptibility to various diseases, including autoimmune, infectious, allergic or cardiovascular diseases. The aim of the current study was to determine allele and genotype frequencies of 22 polymorphisms in 13 cytokine genes in the healthy Slovak population and to compare them with data available from six populations from Central and Southern Europe. A polymerase chain reaction with sequence-specific primers was used to genotype polymorphisms within genes encoding IL-1alpha, IL-1beta, IL-1R, IL-1RA, IL-4Ralpha, IL-12, IFN-gamma, TGF-beta, TNF-alpha, IL-2, IL-4, IL-6 and IL-10 in a sample of 140 unrelated Slovak subjects. The allelic distribution of all polymorphisms in the Slovak population was very close to that in the geographically and historically closest populations in Central Europe--the Czech and the Polish. However, several differences were found between the Slovak and four populations from Southern Europe. The obtained data represent a basis for further studies on association of cytokine gene polymorphisms with some diseases.
17627763	885	894	IL-1alpha	Gene	3552
17627763	896	904	IL-1beta	Gene	3553
17627763	906	911	IL-1R	Gene	-1
17627763	913	919	IL-1RA	Gene	3557
17627763	921	931	IL-4Ralpha	Gene	3566
17627763	933	938	IL-12	Gene	-1
17627763	940	949	IFN-gamma	Gene	3458
17627763	951	959	TGF-beta	Gene	-1
17627763	961	970	TNF-alpha	Gene	7124
17627763	972	976	IL-2	Gene	3558
17627763	978	982	IL-4	Gene	3565
17627763	984	988	IL-6	Gene	3569
17627763	993	998	IL-10	Gene	3586

17636360|t|Identifying haplotype block structure using an ancestor-derived model.
17636360|a|Recently, haplotype-based association studies have become popular for detecting disease-related or drug-response-associated genes. In these studies, it has been gradually recognized that a haplotype block structure is important. A rational and automatic method for identifying the haplotype block structure from SNP data has been desired. We have developed a new method using an ancestor-derived model and the minimum description length principle. The proposed method was applied to real data on the TAP2 gene in which a recombination hotspot was previously reported in human sperm data. The proposed method could identify an appropriate haplotype block structure, while existing methods failed. The performance of the proposed method was also investigated in a simulation study. The proposed method presented a better performance in real data analysis and the simulation study than existing methods. The proposed method was powerful from the viewpoint of hotspot sensitivity and was robust to mutation except at the edge of a sequence.
17636360	571	575	TAP2	Gene	6891

17702016|t|A microduplication of CBP in a patient with mental retardation and a congenital heart defect.
17702016|a|Rubinstein-Taybi syndrome is a well-characterized genetic syndrome caused by haploinsufficiency of CBP in a majority of individuals. In 10% of cases a microdeletion in 16p13.3 affecting CBP is detected. We report on a patient with a de novo 345-480 kb micro-duplication the region, encompassing only CBP and TRAP1. This boy presented with various minor physical anomalies, moderate mental retardation, and an atrial septal defect, but none of the other typical characteristics of the Rubinstein-Taybi syndrome, such as the broad thumbs and first toes or facial characteristics. This finding implicates CBP as one of the causative genes for the trisomy 16p13 syndrome, and indicates this is a contiguous gene syndrome.
17702016	22	25	CBP	Gene	1387
17702016	193	196	CBP	Gene	1387
17702016	280	283	CBP	Gene	1387
17702016	394	397	CBP	Gene	1387
17702016	402	407	TRAP1	Gene	10131
17702016	696	699	CBP	Gene	1387

17854670|t|Myxoinflammatory fibroblastic sarcoma showing t(2;6)(q31;p21.3) as a sole cytogenetic abnormality.
17854670|a|Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare, low-grade sarcoma characterized by distinctive, large, and bizarre Reed--Sternberg--like cells associated with an intense inflammatory infiltrate. The biology of MIFS is still poorly understood, and only two previous cases had been studied cytogenetically. In the present case, analysis of MIFS in the foot of a 53-year-old man revealed the chromosome translocation t(2;6)(q31;p21.3) as the only cytogenetic abnormality. This finding is distinct from the two cases previously reported. Additional studies are needed to verify whether any of these chromosome rearrangements are involved recurrently in MIFS.

17877751|t|Identities, frequencies and origins of TMC1 mutations causing DFNB7/B11 deafness in Pakistan.
17877751|a|Non-syndromic deafness is genetically heterogeneous. We previously reported that mutations of transmembrane channel-like gene 1 (TMC1) cause non-syndromic recessive deafness at the DFNB7/B11 locus on chromosome 9q13-q21 in nine Pakistani families. The goal of this study was to define the identities, origins and frequencies of TMC1 mutations in an expanded cohort of 557 large Pakistani families segregating recessive deafness. We screened affected family members for homozygosity at short-tandem repeats flanking known autosomal recessive (DFNB) deafness loci, followed by TMC1 sequence analysis in families segregating deafness linked to DFNB7/B11. We identified 10 new families segregating DFNB7/B11 deafness and TMC1 mutations, including three novel alleles. Overall, 9 different TMC1 mutations account for deafness in 19 (3.4%) of the 557 Pakistani families. A single mutation, p.R34X, causes deafness in 10 (1.8%) of the families. Genotype analysis of p.R34X-linked markers indicates that it arose from a common founder. We also detected p.R34X among normal control samples of African-American and northern European origins, raising the possibility that p.R34X and other mutations of TMC1 are prevalent contributors to the genetic load of deafness across a variety of populations and continents.
17877751	39	43	TMC1	Gene	117531
17877751	62	67	DFNB7	Gene	117531
17877751	62	71	DFNB7/B11	Gene	117531
17877751	188	221	transmembrane channel-like gene 1	Gene	117531
17877751	223	227	TMC1	Gene	117531
17877751	275	280	DFNB7	Gene	117531
17877751	275	284	DFNB7/B11	Gene	117531
17877751	422	426	TMC1	Gene	117531
17877751	669	673	TMC1	Gene	117531
17877751	735	740	DFNB7	Gene	117531
17877751	735	744	DFNB7/B11	Gene	117531
17877751	788	793	DFNB7	Gene	117531
17877751	788	797	DFNB7/B11	Gene	117531
17877751	811	815	TMC1	Gene	117531
17877751	879	883	TMC1	Gene	117531
17877751	1285	1289	TMC1	Gene	117531

17885622|t|Pharmacokinetic and pharmacodynamic basis for partial protection against alcoholism in Asians, heterozygous for the variant ALDH2*2 gene allele.
17885622|a|OBJECTIVES: It has been well documented that although homozygosity of the variant aldehyde dehydrogenase-2 (ALDH2) gene allele, ALDH2*2, in Asians almost fully protects against alcoholism, the heterozygosity only affords a partial protection to varying degrees. The full protection against alcoholism has been ascribed to the low-amount of alcohol hypersensitivity accompanied by a prolonged and large accumulation of acetaldehyde in blood (Peng et al. Pharmacogenetics 1999; 9:463-476). The physiological basis for the partial protection, however, remains unclear. METHODS: To address this question, we recruited a total of 32 adult Han Chinese men, matched by age, body-mass index, and nutritional state from a population base of 404 men. The subjects were divided into 3 combinatorial genotypic groups of alcohol dehydrogenase (ADH) and ALDH, that is, ALDH2*1/*1-ADH1B*1/*1-ADH1C*1/*1 (n=8), ALDH2*1/*1-ADH1B*2/*2-ADH1C*1/*1 (n=8), and ALDH2*1/*2-ADH1B*2/*2-ADH1C*1/*1 (n=16). Following a moderate dose of ethanol (0.5 g/kg body weight), blood ethanol/acetaldehyde/acetate concentrations, cardiac and extracranial/intracranial arterial hemodynamic parameters, as well as self-rated subjective sensations, were measured for 130 min. RESULTS: Heterozygotic ALDH2*1/*2 subjects were found to be strikingly responsive to the moderate amount of alcohol, as evidenced by the prominent cardiovascular effects as well as subjective perceptions of general discomfort for as long as 2 h following ingestion. The ADH1B polymorphisms did not appear to correlate with the pharmacokinetic and pharmacodynamic effects. CONCLUSIONS: These results indicate that acetaldehyde, rather than ethanol or acetate, is primarily responsible for the observed alcohol sensitivity reactions and suggest that substantially lower accumulation of blood acetaldehyde in the heterozygotes significantly reduces the aversion reaction to low amounts of alcohol that permits other biological as well as environmental factors to facilitate drinking and the according risk for the disease.
17885622	124	129	ALDH2	Gene	217
17885622	227	251	aldehyde dehydrogenase-2	Gene	217
17885622	253	258	ALDH2	Gene	217
17885622	273	278	ALDH2	Gene	217
17885622	1000	1005	ALDH2	Gene	217
17885622	1011	1016	ADH1B	Gene	125
17885622	1022	1027	ADH1C	Gene	126
17885622	1040	1045	ALDH2	Gene	217
17885622	1051	1056	ADH1B	Gene	125
17885622	1062	1067	ADH1C	Gene	126
17885622	1084	1089	ALDH2	Gene	217
17885622	1095	1100	ADH1B	Gene	125
17885622	1106	1111	ADH1C	Gene	126
17885622	1403	1408	ALDH2	Gene	217
17885622	1650	1655	ADH1B	Gene	125

17889706|t|Identification of rare variants in the hLIMD1 gene in breast cancer.
17889706|a|The hLIMD1 gene is located at chromosome 3p21 and was identified as a putative tumor suppressor gene using an elimination test assay. Chromosome 3p21 loci are frequently deleted in a number of cancers, including breast. The 3p21.3 locus harbors a number of tumor suppressor candidates, including LIMD1, a member of the ZYXIN family of genes. LIMD1 directly interacts with RB and is thought to play a role in suppressing tumor growth. To investigate whether mutations in the LIMD1 gene could potentially be involved in breast cancer, we used single-stranded conformation polymorphism analysis on DNA from 235 breast cancers and 95 controls. We identified four novel coding region alterations, including two amino acid substitutions at positions 255 and 302. The two remaining novel variants were found at amino acid positions 246 and 647 and encoded silent alterations. The rare Ser255Arg variant was identified in only sporadic breast tumors (2/165 tumors). Some ZYXIN proteins are phosphorylated by serine/threonine kinases, and the Ser255Arg change is located in a region phosphorylated on serine residues. Together, the data suggest that this variant may warrant further characterization.
17889706	39	45	hLIMD1	Gene	8994
17889706	73	79	hLIMD1	Gene	8994
17889706	365	370	LIMD1	Gene	8994
17889706	388	393	ZYXIN	Gene	7791
17889706	411	416	LIMD1	Gene	8994
17889706	543	548	LIMD1	Gene	8994
17889706	1032	1037	ZYXIN	Gene	7791

17910067|t|Kidney failure in Townes-Brocks syndrome: an under recognized phenomenon?
17910067|a|Though uncommon, kidney malformations are described in several cases of Townes-Brocks syndrome. By contrast, kidney failure has been reported as the presenting feature of Townes-Brocks syndrome on only one occasion. While the SALL1 gene, mutations of which result in the Townes-Brocks phenotype, is expressed in the developing kidney, the absence of other corroborative reports of kidney failure presenting in affected individuals suggests that the solitary observation of kidney failure is as likely due to chance as to causal association. In now reporting a further instance of this association, we review the literature, demonstrating that several other instances of kidney failure are in fact known, despite an incomplete dataset. These findings suggest that kidney failure may be a constituent element of the natural history of Townes-Brocks syndrome and raise the possible benefits of longitudinal survey for progressive kidney impairment in patients with this syndrome.
17910067	300	305	SALL1	Gene	6299

17990063|t|Clinical and molecular characterization of Italian patients affected by Cohen syndrome.
17990063|a|Cohen syndrome is an autosomal recessive disorder with variability in the clinical manifestations, characterized by developmental delay, visual disability, facial dysmorphisms and intermittent neutropenia. We described a cohort of 10 patients affected by Cohen syndrome from nine Italian families ranging from 5 to 52 years at assessment. Characteristic age related facial changes were well documented. Visual anomalies, namely retinopathy and myopia, were present in 9/10 patients (retinopathy in 9/10 and myopia in 8/10). Truncal obesity has been described in all patients older than 6 years (8/8). DNA samples from all patients were analyzed for mutations in COH1 by DHPLC. We detected 15 COH1 alterations most of them were truncating mutations, only one being a missense change. Partial gene deletions have been found in two families. Most mutations were private. Two were already reported in the literature just once. A single base deletion leading to p.T3708fs3769, never reported before, was found in three apparently unrelated families deriving from a restricted area of the Veneto's lowland, between Padova town and Tagliamento river, in heterozygous state. Given the geographical conformation of this region, which is neither geographically or culturally isolated, a recent origin of the mutation could be hypothesized.
17990063	750	754	COH1	Gene	157680
17990063	780	784	COH1	Gene	157680

18000905|t|Regional analysis on the occurrence of oral clefts in South America.
18000905|a|The aim of this work was to search for unequal birth prevalence rates (BPRs) of cleft lip +/- cleft palate (CL/P), and cleft palate only (CPO), among different geographic areas in South America, and to analyze phenotypic characteristics and associated risk factors in each identified cluster. Included were 5,128 CL/P cases, 1,745 CPO cases, and 3,712 controls (like-sexed, non-malformed liveborn infant, born immediately after a malformed one, in the same hospital), over 4,199,630 consecutive births. They were ascertained between 1967 and 2004, in 190 maternity hospitals of the ECLAMC (Estudio Colaborativo Latinoamericano de Malformaciones Congénitas) network, in 102 cities of all 10 South American countries. Non-predefined geographical areas with significantly unusual cleft BPRs were identified with Kulldorf and Nagarwalla's spatial scan statistic, employing number of cases and births, and exact location of each hospital. Expected values were cleft BPRs registered for the entire ECLAMC hospital network. Syndromic and non-syndromic clefts were considered for cluster analysis, and phenotypic characterization, while only non-syndromic for risk factor analysis. Seven clusters for CL/P, and four for CPO, with unusual BPRs were identified. CL/P cases in high BPR areas were more severe than elsewhere in the sample, similar to a previous ECLAMC report on microtia. For CL/P, high BPR clusters were associated with high altitude above sea level, Amerindian ancestry, and low socioeconomic strata; low BPR clusters showed association with African Black ancestry. Advanced maternal age, a recognized risk factor for CPO, was also associated with the only identified geographic cluster for CPO.
18000905	1516	1519	sea	Gene	6395

18063669|t|Evidence that common variation in NEDD9 is associated with susceptibility to late-onset Alzheimer's and Parkinson's disease.
18063669|a|Late-onset Alzheimer's disease (LOAD) and Parkinson's disease (PD) are the most common neurodegenerative disorders and in both diseases susceptibility is known to be influenced by genes. We set out to identify novel susceptibility genes for LOAD by performing a large scale, multi-tiered association study testing 4692 single nucleotide polymorphism (SNPs). We identified a SNP within a putative transcription factor binding site in the NEDD9 gene (neural precursor cell expressed, developmentally down-regulated), that shows good evidence of association with disease risk in four out of five LOAD samples [N = 3521, P = 5.38x10(-6), odds ratio (OR) = 1.38 (1.20-1.59)] and in addition, we observed a similar pattern of association in two PD sample sets [N = 1464, P = 0.0145, OR =1.31 (1.05-1.62)]. In exploring a potential mechanism for the association, we observed that expression of NEDD9 and APOE show a strong inverse correlation in the hippocampus of Alzheimer's cases. These data implicate NEDD9 as a novel susceptibility gene for LOAD and possibly PD.
18063669	34	39	NEDD9	Gene	4739
18063669	562	567	NEDD9	Gene	4739
18063669	1012	1017	NEDD9	Gene	4739
18063669	1022	1026	APOE	Gene	348
18063669	1123	1128	NEDD9	Gene	4739

18075470|t|Association between caffeine intake and risk of Parkinson's disease among fast and slow metabolizers.
18075470|a|INTRODUCTION: Cytochrome P450 1A2 (CYP 1A2) is responsible for more than 90% of caffeine clearance. A polymorphic variant of CYP1A2 (-163C>A) (rs762551) is associated with high CYP1A2 inducibility. Both caffeine and its main metabolite, paraxanthine, may be neuroprotective. The association between caffeine intake and risk of Parkinson's disease (PD) in fast and slow caffeine metabolizers has not been compared. OBJECTIVE: In a case-control study, we analyzed the relationship between caffeine intake and risk of PD in both fast and slow caffeine metabolizers. METHODS: All the study participants were recruited prospectively, and interviewed for information on the amount and duration of caffeine intake. Genotyping of the CYP1A2 variant was carried out using the allelic discrimination method. RESULTS: Out of 1000 participants who were initially screened, 886 consisting of 418 PD and 468 race, sex and age matched controls were included. No evidence existed to suggest any association between CYP1A2 and the onset of PD (P=0.08). A significant association was seen between caffeine intake and the onset of PD (P=2.01x10(-5)), with the odds ratio for moderate and high drinkers at 0.71 [95% confidence interval (CI): 0.50-1.00] and 0.47 (95% CI: 0.34-0.65), respectively against the low drinkers. Multivariate analysis revealed no evidence of any interaction effects of caffeine with CYP1A2 (P=0.956). CONCLUSION: The association between caffeine intake and risk of PD was similarly observed in both fast and slow caffeine metabolizers, supporting experimental evidence in animal models that both caffeine and its major metabolite, paraxanthine, are neuroprotective.
18075470	116	135	Cytochrome P450 1A2	Gene	1544
18075470	137	144	CYP 1A2	Gene	1544
18075470	227	233	CYP1A2	Gene	1544
18075470	279	285	CYP1A2	Gene	1544
18075470	828	834	CYP1A2	Gene	1544
18075470	1101	1107	CYP1A2	Gene	1544
18075470	1491	1497	CYP1A2	Gene	1544

18179903|t|Mutation analysis of CHRNA1, CHRNB1, CHRND, and RAPSN genes in multiple pterygium syndrome/fetal akinesia patients.
18179903|a|Multiple pterygium syndromes (MPS) comprise a group of multiple congenital anomaly disorders characterized by webbing (pterygia) of the neck, elbows, and/or knees and joint contractures (arthrogryposis). MPS are phenotypically and genetically heterogeneous but are traditionally divided into prenatally lethal and nonlethal (Escobar) types. Previously, we and others reported that recessive mutations in the embryonal acetylcholine receptor g subunit (CHRNG) can cause both lethal and nonlethal MPS, thus demonstrating that pterygia resulted from fetal akinesia. We hypothesized that mutations in acetylcholine receptor-related genes might also result in a MPS/fetal akinesia phenotype and so we analyzed 15 cases of lethal MPS/fetal akinesia without CHRNG mutations for mutations in the CHRNA1, CHRNB1, CHRND, and rapsyn (RAPSN) genes. No CHRNA1, CHRNB1, or CHRND mutations were detected, but a homozygous RAPSN frameshift mutation, c.1177-1178delAA, was identified in a family with three children affected with lethal fetal akinesia sequence. Previously, RAPSN mutations have been reported in congenital myasthenia. Functional studies were consistent with the hypothesis that whereas incomplete loss of rapsyn function may cause congenital myasthenia, more severe loss of function can result in a lethal fetal akinesia phenotype.
18179903	21	27	CHRNA1	Gene	1134
18179903	29	35	CHRNB1	Gene	1140
18179903	37	42	CHRND	Gene	1144
18179903	48	53	RAPSN	Gene	5913
18179903	524	566	embryonal acetylcholine receptor g subunit	Gene	1146
18179903	568	573	CHRNG	Gene	1146
18179903	867	872	CHRNG	Gene	1146
18179903	904	910	CHRNA1	Gene	1134
18179903	912	918	CHRNB1	Gene	1140
18179903	920	925	CHRND	Gene	1144
18179903	931	937	rapsyn	Gene	5913
18179903	939	944	RAPSN	Gene	5913
18179903	956	962	CHRNA1	Gene	1134
18179903	964	970	CHRNB1	Gene	1140
18179903	975	980	CHRND	Gene	1144
18179903	1023	1028	RAPSN	Gene	5913
18179903	1173	1178	RAPSN	Gene	5913
18179903	1321	1327	rapsyn	Gene	5913

18203180|t|Paternal deletion 6q24.3: a new congenital anomaly syndrome associated with intrauterine growth failure, early developmental delay and characteristic facial appearance.
18203180|a|Deletions of the long arm of chromosome 6 are relatively uncommon and to date minimal genotype-phenotype correlations have been observed. We report on three unrelated patients with de novo paternal interstitial deletions of 6q24.3. FISH mapping was used to delineate the minimal region of overlap between these three patients. Although all three patients had different size deletions and different breakpoints, two of the patients shared a 2.5 Mb region of overlap and strikingly similar facial features including a triangular face, frontal bossing with metopic prominence, short and upward-slanting palpebral fissures, asymmetry of upper eyelids, hooded eyelids, shallow orbits, prominent inferior orbital crease, wide mouth, and long and flat philtrum. They also had redundant skin, joint laxity, a small thorax, and early developmental delay. The smallest region of overlap between all three patients was a region of deletion less than 1 Mb; all had a history of IUGR and postnatal short stature without overt radiologic skeletal anomalies. The dysmorphic features, early developmental and growth delay may be due to the hemizygous state for one of the genes in the deleted region of two of the patients or to a long range effect of the deletion on expression of other genes. In addition, since imprinted genes have been reported in this region, paternal deletion of an imprinted gene in all three patients may contribute to the growth phenotype. We propose that this is a new congenital malformation syndrome associated with a paternal deletion of 6q24.3.

18262054|t|A family with two consecutive nonsense mutations in BMPR1A causing juvenile polyposis.
18262054|a|We describe a novel germline mutation of BMPR1A in a family with juvenile polyposis and colon cancer. This mutation consists of two consecutive substitutions (735-6 TG>AT) that cause two nonsense mutations (Y245X, G246X), inherited in an autosomal dominant fashion, on one parental chromosome. This mutation caused protein truncation, and represents a novel case of consecutive nonsense mutations in human disease.
18262054	52	58	BMPR1A	Gene	657
18262054	128	134	BMPR1A	Gene	657

18366737|t|The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency.
18366737|a|BACKGROUND: Fumarate hydratase (HGNC approved gene symbol - FH), also known as fumarase, is an enzyme of the tricarboxylic acid (TCA) cycle, involved in fundamental cellular energy production. First described by Zinn et al in 1986, deficiency of FH results in early onset, severe encephalopathy. In 2002, the Multiple Leiomyoma Consortium identified heterozygous germline mutations of FH in patients with multiple cutaneous and uterine leiomyomas, (MCUL: OMIM 150800). In some families renal cell cancer also forms a component of the complex and as such has been described as hereditary leiomyomatosis and renal cell cancer (HLRCC: OMIM 605839). The identification of FH as a tumor suppressor was an unexpected finding and following the identification of subunits of succinate dehydrogenase in 2000 and 2001, was only the second description of the involvement of an enzyme of intermediary metabolism in tumorigenesis. DESCRIPTION: The FH mutation database is a part of the TCA cycle gene mutation database (formerly the succinate dehydrogenase gene mutation database) and is based on the Leiden Open (source) Variation Database (LOVD) system. The variants included in the database were derived from the published literature and annotated to conform to current mutation nomenclature. The FH database applies HGVS nomenclature guidelines, and will assist researchers in applying these guidelines when directly submitting new sequence variants online. Since the first molecular characterization of an FH mutation by Bourgeron et al in 1994, a series of reports of both FH deficiency patients and patients with MCUL/HLRRC have described 107 variants, of which 93 are thought to be pathogenic. The most common type of mutation is missense (57%), followed by frameshifts & nonsense (27%), and diverse deletions, insertions and duplications. Here we introduce an online database detailing all reported FH sequence variants. CONCLUSION: The FH mutation database strives to systematically unify all current genetic knowledge of FH variants. We believe that this knowledge will assist clinical geneticists and treating physicians when advising patients and their families, will provide a rapid and convenient resource for research scientists, and may eventually assist in gaining novel insights into FH and its related clinical syndromes.
18366737	4	6	FH	Gene	2271
18366737	48	66	fumarate hydratase	Gene	2271
18366737	136	144	fumarase	Gene	2271
18366737	169	187	Fumarate hydratase	Gene	2271
18366737	217	219	FH	Gene	2271
18366737	236	244	fumarase	Gene	2271
18366737	403	405	FH	Gene	2271
18366737	542	544	FH	Gene	2271
18366737	825	827	FH	Gene	2271
18366737	1092	1094	FH	Gene	2271
18366737	1444	1446	FH	Gene	2271
18366737	1655	1657	FH	Gene	2271
18366737	1723	1725	FH	Gene	2271
18366737	2052	2054	FH	Gene	2271
18366737	2090	2092	FH	Gene	2271
18366737	2176	2178	FH	Gene	2271
18366737	2447	2449	FH	Gene	2271

18406868|t|Genetic heterogeneity by comparative genomic hybridization in BRCAx breast cancers.
18406868|a|The chromosomal changes in eight familial BRCAx breast cancers (i.e., negative for BRCA1 or BRCA2) were analyzed by comparative genomic hybridization (CGH) to investigate intratumor heterogeneity. This was the first step in a study of most frequent chromosomal aberrations in BRCAx familial breast cancers. Laser microdissection analysis of paraffin tissue samples was followed by whole-genome amplification. CGH was performed on DNA isolated from two to three different cell groups per case to detect any cytogenetic aberrations in important clones that might have been missed when analyzing DNA extracted from large numbers of cells. The results were compared, to evaluate the influence of tumor heterogeneity on CGH, and the heterogeneity was confirmed comparing CGH with fluorescence in situ hybridization results. Different chromosomal aberrations were detected between adjacent clones within the same section, which highlights the utility of microdissection in addressing the problem of heterogeneity in whole-genome studies. Some chromosomal regions were more frequently altered in the eight BRCAx tumors; loss of 2q, 3p, 3q, 8p, 9p, and 15q and gains of 1p, 4p, 4q, 5p, 6q, 12q, and 19p were the most common. Further studies focusing on specific genes and sequences with more sensitive approaches, such as array-CGH, are warranted to confirm these findings.
18406868	167	172	BRCA1	Gene	672
18406868	176	181	BRCA2	Gene	675

18409191|t|The infevers autoinflammatory mutation online registry: update with new genes and functions.
18409191|a|Infevers (Internet Fevers; http://fmf.igh.cnrs.fr/ISSAID/infevers), a website dedicated to mutations responsible for hereditary autoinflammatory diseases, was created in 2002 and has continued to evolve. This new version includes eight genes; six were already present: MEFV, MVK, TNFRSF1A, NLRP3, NOD2, PSTPIP1, and two are new, LPIN2 and NLRP7. Currently, Infevers contains over 540 sequence variants. Several new database functions were recently instituted. The website now accepts confidential data and complex alleles. For each gene, a newly created menu offers: 1) a tabular list of the variants that can be sorted by several parameters; 2) a gene graph providing a schematic representation of the variants along the gene; 3) statistical analysis of the data according to the phenotype, alteration type, and location of the mutation in the gene; 4) the cDNA and gDNA sequences of each gene, showing the nucleotide changes along the sequence, with a color-based code highlighting the gene domains, the first ATG, and the termination codon; and 5) a "download" menu making all tables and figures available for the users, which, except for the gene graphs, are all automatically generated and updated upon submission of the variants. Finally, the entire database was curated to comply with the HUGO Gene Nomenclature Committee (HGNC) and HGVS nomenclature guidelines, and wherever necessary, an informative note was provided. Infevers has already proven useful for the scientific community with a mean number of visits per month of 200 in 2002 and 800 in 2007, and its new design will lead to a more comprehensive comparative analysis and interpretation of auto-inflammatory sequence variants.
18409191	362	366	MEFV	Gene	4210
18409191	368	371	MVK	Gene	4598
18409191	373	381	TNFRSF1A	Gene	7132
18409191	383	388	NLRP3	Gene	114548
18409191	390	394	NOD2	Gene	64127
18409191	396	403	PSTPIP1	Gene	9051
18409191	422	427	LPIN2	Gene	9663
18409191	432	437	NLRP7	Gene	199713

18466102|t|CYP2E1 polymorphisms and gene-environment interactions in the risk of upper aerodigestive tract cancers among Indians.
18466102|a|INTRODUCTION: The CYP2E1 enzyme is responsible for the metabolic activation of several procarcinogens into reactive metabolites that result in carcinogenesis. The genetic polymorphisms that modify these enzymatic activities may be associated with upper aerodigestive tract cancer risk. METHODS: This hospital-based study evaluated CYP2E1*1B, CYP2E1*5B and CYP2E1*6 polymorphisms in 408 histopathologically confirmed cases and 220 population-based controls using PCR-RFLP methods. RESULTS: The multivariate logistic regression analyses demonstrated no significant differences between groups for all three polymorphisms when analyzed separately. However, the gene-environment interactions analyses revealed significant interactions among tobacco smokers (11-20 pack years), 20-40 pack years and > 40 pack years), regular tobacco chewers and alcoholics carrying CYP2E1*1B mutant genotypes. Similarly, CYP2E1*6 polymorphisms resulted in significant interactions among tobacco smokers (> 40 pack years) and regular tobacco chewers on the multiplicative scale. CONCLUSION: The significant gene-environment interactions observed for CYP2E1*1B and CYP2E1*6 polymorphic genotypes may confer a substantial risk for upper aerodigestive tract cancers among Indians.
18466102	0	6	CYP2E1	Gene	1571
18466102	137	143	CYP2E1	Gene	1571
18466102	450	456	CYP2E1	Gene	1571
18466102	461	467	CYP2E1	Gene	1571
18466102	475	481	CYP2E1	Gene	1571
18466102	978	984	CYP2E1	Gene	1571
18466102	1017	1023	CYP2E1	Gene	1571
18466102	1245	1251	CYP2E1	Gene	1571
18466102	1259	1265	CYP2E1	Gene	1571

18487244|t|Depletion of mitochondrial DNA in fibroblast cultures from patients with POLG1 mutations is a consequence of catalytic mutations.
18487244|a|We investigated clinical and cellular phenotypes of 24 children with mutations in the catalytic (alpha) subunit of the mitochondrial DNA (mtDNA) gamma polymerase (POLG1). Twenty-one had Alpers syndrome, the commonest severe POLG1 autosomal recessive phenotype, comprising hepatoencephalopathy and often mtDNA depletion. The cellular mtDNA content reflected the genotype more closely than did clinical features. Patients with tissue depletion of mtDNA all had at least one allele with either a missense mutation in a catalytic domain or a nonsense mutation. Four out of 12 patients exhibited a progressive, mosaic pattern of mtDNA depletion in cultured fibroblasts. All these patients had mutations in a catalytic domain in both POLG1 alleles, in either the polymerase or exonuclease domain or both. The tissue mtDNA content of patients who had two linker mutations was normal, and their phenotypes the mildest. Epilepsy and/or movement disorder were major features in all 21. Previous studies have implicated replication stalling as a mechanism for mtDNA depletion. The mosaic cellular depletion that we have demonstrated in cell cultures may be a manifestation of severe replication stalling. One patient with a severe cellular and clinical phenotype was a compound heterozygote with POLG1 mutations in the polymerase and exonuclease domain intrans. This suggests that POLG1 requires both polymerase and 3'-5' exonuclease activity in the same molecule. This is consistent with current functional models for eukaryotic DNA polymerases, which alternate between polymerizing and editing modes, as determined by competition between these two active sites for the 3' end of the DNA.
18487244	73	78	POLG1	Gene	5428
18487244	249	291	mitochondrial DNA (mtDNA) gamma polymerase	Gene	5428
18487244	293	298	POLG1	Gene	5428
18487244	354	359	POLG1	Gene	5428
18487244	858	863	POLG1	Gene	5428
18487244	1415	1420	POLG1	Gene	5428
18487244	1500	1505	POLG1	Gene	5428

18521840|t|Identification of novel dyslexia candidate genes through the analysis of a chromosomal deletion.
18521840|a|Dyslexia is the most common childhood learning disorder and it is a significantly heritable trait. At least nine chromosomal loci have been linked to dyslexia, and additional susceptibility loci on other chromosomes have been suggested. Within two of these loci, DYX1C1 (15q21) and ROBO1 (3p12) have recently been proposed as dyslexia candidate genes through the molecular analysis of translocation breakpoints in dyslexic individuals carrying balanced chromosomal translocations. Moreover, genetic association studies have indicated a cluster of five dyslexia candidate genes in another linkage region on chromosome 6p22, although there is currently no consensus about which of these five genes contributes to the genetic susceptibility for dyslexia. In this article, we report the identification of four new dyslexia candidate genes (PCNT, DIP2A, S100B, and PRMT2) on chromosome region 21q22.3 by FISH and SNP microarray analyses of a very small deletion in this region, which cosegregates with dyslexia in a father and his three sons.
18521840	360	366	DYX1C1	Gene	161582
18521840	379	384	ROBO1	Gene	6091
18521840	933	937	PCNT	Gene	5116
18521840	939	944	DIP2A	Gene	23181
18521840	946	951	S100B	Gene	6285
18521840	957	962	PRMT2	Gene	3275

18543312|t|Granulin mutations associated with frontotemporal lobar degeneration and related disorders: an update.
18543312|a|Mutations in the gene encoding granulin (HUGO gene symbol GRN, also referred to as progranulin, PGRN), located at chromosome 17q21, were recently linked to tau-negative ubiquitin-positive frontotemporal lobar degeneration (FTLDU). Since then, 63 heterozygous mutations were identified in 163 families worldwide, all leading to loss of functional GRN, implicating a haploinsufficiency mechanism. Together, these mutations explained 5 to 10% of FTLD. The high mutation frequency, however, might still be an underestimation because not all patient samples were examined for all types of loss-of-function mutations and because several variants, including missense mutations, have a yet uncertain pathogenic significance. Although the complete phenotypic spectrum associated with GRN mutations is not yet fully characterized, it was shown that it is highly heterogeneous, suggesting the influence of modifying factors. A role of GRN in neuronal survival was suggested but the exact mechanism by which neurodegeneration and deposition of pathologic brain inclusions occur still has to be clarified.
18543312	0	8	Granulin	Gene	2896
18543312	134	142	granulin	Gene	2896
18543312	161	164	GRN	Gene	2896
18543312	186	197	progranulin	Gene	2896
18543312	199	203	PGRN	Gene	2896
18543312	449	452	GRN	Gene	2896
18543312	878	881	GRN	Gene	2896
18543312	1027	1030	GRN	Gene	2896

18648394|t|LDLR promoter variant and exon 14 mutation on the same chromosome are associated with an unusually severe FH phenotype and treatment resistance.
18648394|a|Familial hypercholesterolemia (FH) is the most common form of autosomal-dominant hypercholesterolemia, and is caused by mutations in the low-density lipoprotein receptor (LDLR) gene. Heterozygous FH is characterized by elevated low-density lipoprotein (LDL) cholesterol and early-onset cardiovascular disease, whereas homozygous FH results in more severe LDL cholesterol elevation with death by 20 years of age. We present here the case of an African-American female FH patient presenting with a myocardial infarction at the age of 48, recurrent angina pectoris and numerous coronary artery stents. Her pretreated LDL cholesterol levels were more typical of a homozygous FH pattern and she was resistant to conventional lipid-lowering treatment, yet her other clinical parameters were not necessarily consistent with homozygous FH. Genetic testing revealed two LDLR variants on the same chromosome: one a novel missense mutation in exon 14 (Cys681Gly) and the other a promoter variant (IVS1-217C>T) previously shown to result in increased LDLR transcription. Disease-associated PCSK9 or APOB mutations were not identified in this individual. Overall, her genetic and clinical profile suggests that enhanced expression of the mutant LDLR allele resulted in a severe phenotype with characteristics of both heterozygous and homozygous FH.
18648394	0	4	LDLR	Gene	3949
18648394	282	314	low-density lipoprotein receptor	Gene	3949
18648394	316	320	LDLR	Gene	3949
18648394	1006	1010	LDLR	Gene	3949
18648394	1184	1188	LDLR	Gene	3949
18648394	1223	1228	PCSK9	Gene	255738
18648394	1232	1236	APOB	Gene	338
18648394	1377	1381	LDLR	Gene	3949

18772193|t|Novel suppressors of alpha-synuclein toxicity identified using yeast.
18772193|a|The mechanism by which the Parkinson's disease-related protein alpha-synuclein (alpha-syn) causes neurodegeneration has not been elucidated. To determine the genes that protect cells from alpha-syn, we used a genetic screen to identify suppressors of the super sensitivity of the yeast Saccharomyces cerevisiae expressing alpha-syn to killing by hydrogen peroxide. Forty genes in ubiquitin-dependent protein catabolism, protein biosynthesis, vesicle trafficking and the response to stress were identified. Five of the forty genes--ENT3, IDP3, JEM1, ARG2 and HSP82--ranked highest in their ability to block alpha-syn-induced reactive oxygen species accumulation, and these five genes were characterized in more detail. The deletion of any of these five genes enhanced the toxicity of alpha-syn as judged by growth defects compared with wild-type cells expressing alpha-syn, which indicates that these genes protect cells from alpha-syn. Strikingly, four of the five genes are specific for alpha-syn in that they fail to protect cells from the toxicity of the two inherited mutants A30P or A53T. This finding suggests that alpha-syn causes toxicity to cells through a different pathway than these two inherited mutants. Lastly, overexpression of Ent3p, which is a clathrin adapter protein involved in protein transport between the Golgi and the vacuole, causes alpha-syn to redistribute from the plasma membrane into cytoplasmic vesicular structures. Our interpretation is that Ent3p mediates the transport of alpha-syn to the vacuole for proteolytic degradation. A similar clathrin adaptor protein, epsinR, exists in humans.
18772193	21	36	alpha-synuclein	Gene	6622
18772193	133	148	alpha-synuclein	Gene	6622
18772193	150	159	alpha-syn	Gene	6622
18772193	258	267	alpha-syn	Gene	6622
18772193	392	401	alpha-syn	Gene	6622
18772193	601	605	ENT3	Gene	853589
18772193	607	611	IDP3	Gene	855723
18772193	613	617	JEM1	Gene	853372
18772193	619	623	ARG2	Gene	853374
18772193	628	633	HSP82	Gene	855836
18772193	676	685	alpha-syn	Gene	6622
18772193	853	862	alpha-syn	Gene	6622
18772193	932	941	alpha-syn	Gene	6622
18772193	995	1004	alpha-syn	Gene	6622
18772193	1058	1067	alpha-syn	Gene	6622
18772193	1191	1200	alpha-syn	Gene	6622
18772193	1314	1319	Ent3p	Gene	853589
18772193	1429	1438	alpha-syn	Gene	6622
18772193	1546	1551	Ent3p	Gene	853589
18772193	1578	1587	alpha-syn	Gene	6622
18772193	1668	1674	epsinR	Gene	9685

18794729|t|Polymorphism of the hepatic influx transporter organic anion transporting polypeptide 1B1 is associated with increased cholesterol synthesis rate.
18794729|a|We investigated the influence of SLCO1B1 polymorphism on cholesterol synthesis and absorption during baseline, and as affected by statins. In a crossover study, 32 healthy volunteers with different SLCO1B1 genotypes ingested a single dose of fluvastatin, pravastatin, simvastatin, rosuvastatin, and atorvastatin. Plasma total cholesterol, and cholesterol synthesis and absorption markers were measured before statin administration and up to 12 h thereafter. The mean fasting baseline plasma desmosterol to cholesterol ratio was 40% higher in participants with the SLCO1B1 c.521CC variant genotype than in those with the c.521TT genotype (P=0.043). The genotype had no significant effect on cholesterol absorption markers. All statins decreased lathosterol and avenasterol to cholesterol ratios, but no significant differences in the response existed between SLCO1B1 genotypes. In conclusion, the low activity SLCO1B1 c.521CC genotype is associated with an increased cholesterol synthesis rate. The short-term effects of statins on cholesterol homeostasis were not associated with the SLCO1B1 polymorphism.
18794729	20	89	hepatic influx transporter organic anion transporting polypeptide 1B1	Gene	10599
18794729	180	187	SLCO1B1	Gene	10599
18794729	345	352	SLCO1B1	Gene	10599
18794729	711	718	SLCO1B1	Gene	10599
18794729	1005	1012	SLCO1B1	Gene	10599
18794729	1056	1063	SLCO1B1	Gene	10599
18794729	1231	1238	SLCO1B1	Gene	10599

18805828|t|Association of a null allele of SPRN with variant Creutzfeldt-Jakob disease.
18805828|a|BACKGROUND: No susceptibility genes have been identified in human prion disase, apart from the prion protein gene (PRNP). The gene SPRN, encodes Shadoo (Sho, shadow of prion protein) which has protein homology and possible functional links with the prion protein. METHODS: A genetic screen was carried out of the open reading frame of SPRN by direct sequencing in 522 patients with prion disease, including 107 with variant Creutzfeldt-Jakob disease (vCJD), and 861 healthy controls. RESULTS: A common coding variant of SPRN, two further single nucleotide polymorphisms (SNPs) and three rare insertion or deletion variants were found. A single base-pair insertion at codon 46, predicted to cause a frameshift and potentially a novel protein, was found in two patients with vCJD but not in controls (p = 0.01). Two linked SNPs, one in intron 1 and the other a missense variant at codon 7, were associated with risk of sporadic CJD (p = 0.009). CONCLUSION: These data justify the functional genetic characterisation of SPRN and support the involvement of Shadoo in prion pathobiology.
18805828	32	36	SPRN	Gene	503542
18805828	172	185	prion protein	Gene	5621
18805828	192	196	PRNP	Gene	5621
18805828	208	212	SPRN	Gene	503542
18805828	222	228	Shadoo	Gene	503542
18805828	230	233	Sho	Gene	503542
18805828	235	258	shadow of prion protein	Gene	503542
18805828	326	339	prion protein	Gene	5621
18805828	412	416	SPRN	Gene	503542
18805828	597	601	SPRN	Gene	503542
18805828	1094	1098	SPRN	Gene	503542
18805828	1130	1136	Shadoo	Gene	503542

18951438|t|Locus-specific databases and recommendations to strengthen their contribution to the classification of variants in cancer susceptibility genes.
18951438|a|Locus-specific databases (LSDBs) are curated collections of sequence variants in genes associated with disease. LSDBs of cancer-related genes often serve as a critical resource to researchers, diagnostic laboratories, clinicians, and others in the cancer genetics community. LSDBs are poised to play an important role in disseminating clinical classification of variants. The IARC Working Group on Unclassified Genetic Variants has proposed a new system of five classes of variants in cancer susceptibility genes. However, standards are lacking for reporting and analyzing the multiple data types that assist in classifying variants. By adhering to standards of transparency and consistency in the curation and annotation of data, LSDBs can be critical for organizing our understanding of how genetic variation relates to disease. In this article we discuss how LSDBs can accomplish these goals, using existing databases for BRCA1, BRCA2, MSH2, MLH1, TP53, and CDKN2A to illustrate the progress and remaining challenges in this field. We recommend that: 1) LSDBs should only report a conclusion related to pathogenicity if a consensus has been reached by an expert panel. 2) The system used to classify variants should be standardized. The Working Group encourages use of the five class system described in this issue by Plon and colleagues. 3) Evidence that supports a conclusion should be reported in the database, including sources and criteria used for assignment. 4) Variants should only be classified as pathogenic if more than one type of evidence has been considered. 5) All instances of all variants should be recorded.
18951438	1069	1074	BRCA1	Gene	672
18951438	1076	1081	BRCA2	Gene	675
18951438	1083	1087	MSH2	Gene	4436
18951438	1089	1093	MLH1	Gene	4292
18951438	1095	1099	TP53	Gene	7157
18951438	1105	1111	CDKN2A	Gene	1029

18991055|t|Association between polymorphisms in SLC30A8, HHEX, CDKN2A/B, IGF2BP2, FTO, WFS1, CDKAL1, KCNQ1 and type 2 diabetes in the Korean population.
18991055|a|According to recent genome-wide association studies, a number of single nucleotide polymorphisms (SNPs) are reported to be associated with type 2 diabetes mellitus (T2DM). The aim of the present study was to investigate the association among the polymorphisms of SLC30A8, HHEX, CDKN2A/B, IGF2BP2, FTO, WFS1, CDKAL1 and KCNQ1 and the risk of T2DM in the Korean population. This study was based on a multicenter case-control study, including 908 patients with T2DM and 502 non-diabetic controls. We genotyped rs13266634, rs1111875, rs10811661, rs4402960, rs8050136, rs734312, rs7754840 and rs2237892 and measured the body weight, body mass index and fasting plasma glucose in all patients and controls. The strongest association was found in a variant of CDKAL1 [rs7754840, odds ratio (OR) = 1.77, 95% CI = 1.50-2.10, p = 5.0 x 10(-11)]. The G allele of rs1111875 (OR = 1.43, 95% CI = 1.18-1.72, p = 1.8 x 10(-4)) in HHEX), the T allele of rs10811661 (OR = 1.47, 95% CI = 1.23-1.75, p = 2.1 x 10(-5)) in CDKN2A/B) and the C allele of rs2237892 (OR = 1.31, 95% CI = 1.10-1.56, p = 0.003) in KCNQ1 showed significant associations with T2DM. Rs13266634 (OR = 1.19, 95% CI = 1.00-1.42, p = 0.045) in SLC30A8 showed a nominal association with the risk of T2DM, whereas SNPs in IGF2BP2, FTO and WFS1 were not associated. In conclusion, we have shown that SNPs in HHEX, CDKN2A/B, CDKAL1, KCNQ1 and SLC30A8 confer a risk of T2DM in the Korean population.
18991055	37	44	SLC30A8	Gene	169026
18991055	46	50	HHEX	Gene	3087
18991055	52	58	CDKN2A	Gene	1029
18991055	52	60	CDKN2A/B	Gene	1030
18991055	62	69	IGF2BP2	Gene	10644
18991055	71	74	FTO	Gene	79068
18991055	76	80	WFS1	Gene	7466
18991055	82	88	CDKAL1	Gene	54901
18991055	90	95	KCNQ1	Gene	3784
18991055	405	412	SLC30A8	Gene	169026
18991055	414	418	HHEX	Gene	3087
18991055	420	426	CDKN2A	Gene	1029
18991055	420	428	CDKN2A/B	Gene	1030
18991055	430	437	IGF2BP2	Gene	10644
18991055	439	442	FTO	Gene	79068
18991055	444	448	WFS1	Gene	7466
18991055	450	456	CDKAL1	Gene	54901
18991055	461	466	KCNQ1	Gene	3784
18991055	895	901	CDKAL1	Gene	54901
18991055	1057	1061	HHEX	Gene	3087
18991055	1144	1150	CDKN2A	Gene	1029
18991055	1144	1152	CDKN2A/B	Gene	1030
18991055	1230	1235	KCNQ1	Gene	3784
18991055	1336	1343	SLC30A8	Gene	169026
18991055	1412	1419	IGF2BP2	Gene	10644
18991055	1421	1424	FTO	Gene	79068
18991055	1429	1433	WFS1	Gene	7466
18991055	1497	1501	HHEX	Gene	3087
18991055	1503	1509	CDKN2A	Gene	1029
18991055	1503	1511	CDKN2A/B	Gene	1030
18991055	1513	1519	CDKAL1	Gene	54901
18991055	1521	1526	KCNQ1	Gene	3784
18991055	1531	1538	SLC30A8	Gene	169026

19092437|t|Clinical practice and genetic counseling for cystic fibrosis and CFTR-related disorders.
19092437|a|Cystic fibrosis transmembrane conductance regulator-related disorders encompass a disease spectrum from focal male reproductive tract involvement in congenital absence of the vas deferens to multiorgan involvement in classic cystic fibrosis. The reproductive, gastrointestinal, and exocrine manifestations of cystic fibrosis transmembrane conductance regulator deficiency are correlated with CFTR genotype, whereas the respiratory manifestations that are the main cause of morbidity and mortality in cystic fibrosis are less predictable. Molecular genetic testing of CFTR has led to new diagnostic strategies and will enable targeting of molecular therapies now in development. Older diagnostic methods that measure sweat chloride and nasal potential difference nonetheless remain important because of their sensitivity and specificity. In addition, the measurement of immunoreactive trypsinogen and the genotyping of CFTR alleles are key to newborn screening programs because of low cost. The multiorgan nature of cystic fibrosis leads to a heavy burden of care, thus therapeutic regimens are tailored to the specific manifestations present in each patient. The variability of cystic fibrosis lung disease and the variable expressivity of mild CFTR alleles complicate genetic counseling for this autosomal recessive disorder. Widespread implementation of newborn screening programs among populations with significant cystic fibrosis mutation carrier frequencies is expected to result in increasing demands on genetic counseling resources.
19092437	65	69	CFTR	Gene	1080
19092437	89	140	Cystic fibrosis transmembrane conductance regulator	Gene	1080
19092437	398	449	cystic fibrosis transmembrane conductance regulator	Gene	1080
19092437	481	485	CFTR	Gene	1080
19092437	656	660	CFTR	Gene	1080
19092437	1007	1011	CFTR	Gene	1080
19092437	1334	1338	CFTR	Gene	1080

19104840|t|Breakpoint mapping and haplotype analysis of three reciprocal translocations identify a novel recurrent translocation in two unrelated families: t(4;11)(p16.2;p15.4).
19104840|a|The majority of constitutional reciprocal translocations appear to be unique rearrangements arising from independent events. However, a small number of translocations are recurrent, most significantly the t(11;22)(q23;q11). Among large series of translocations there may be multiple independently ascertained cases with the same cytogenetic breakpoints. Some of these could represent additional recurrent rearrangements, alternatively they could be identical by descent (IBD) or have subtly different breakpoints when examined under higher resolution. We have used molecular breakpoint mapping and haplotyping to determine the origin of three pairs of reciprocal constitutional translocations, each with the same cytogenetic breakpoints. FISH mapping showed one pair to have different breakpoints and thus to be distinct rearrangements. Another pair of translocations were IBD with identical breakpoint intervals and highly conserved haplotypes on the derived chromosomes. The third pair, t(4;11)(p16.2;p15.4), had the same breakpoint intervals by aCGH and fosmid mapping but had very different haplotypes, therefore they represent a novel recurrent translocation. Unlike the t(11;22)(q23;q11), the formation of the t(4;11)(p16.2;p15.4) may have involved segmental duplications and sequence homology at the breakpoints. Additional examples of recurrent translocations could be identified if the resources were available to study more translocations using the approaches described here. However, like the t(4;11)(p16.2;p15.4), such translocations are likely to be rare with the t(11;22) remaining the only common recurrent constitutional reciprocal translocation.

19104841|t|Alterations of ROBO1/DUTT1 and ROBO2 loci in early dysplastic lesions of head and neck: clinical and prognostic implications.
19104841|a|Deletion of chromosomal 3p12.3 was suggested to be associated with dysplastic lesions of head and neck. This region harbors two candidate tumor suppressors ROBO1/DUTT1, ROBO2 and two non-coding RNAs (ncRNAs) located at intron 2 of ROBO1/DUTT1. Aim of this study is to understand the role of these genes in development of head and neck squamous cell carcinoma. A collection of 72 dysplastic lesions and 116 HNSCC samples and two oral cancer cell lines were analyzed for ROBO1/DUTT1 and ROBO2 deletion and promoter methylation. ROBO1/DUTT1, ROBO2 and two ncRNAs mRNA expression were analyzed by Q-PCR. Immunohistochemical analysis of ROBO1/DUTT1 and ROBO2 was performed. Alterations of these genes were correlated with different clinicopathological parameters. High frequency of molecular alterations (deletion/methylation) was seen in ROBO1/DUTT1 than ROBO2. In mild dysplastic lesions both of these genes showed high molecular alterations and remained more or less constant in subsequent stages. Q-PCR analysis showed reduced expression of these genes and the two ncRNAs. In vitro demethylation experiment by 5-aza-dC showed upregulation of ROBO1/DUTT1 and ROBO2 while the expression of the ncRNAs remained unchanged. Immunohistochemical analysis of ROBO1/DUTT1 and ROBO2 showed concordance with their mRNA expression and molecular alterations. Poor patients' outcome was predicted in the cases with alteration of ROBO1/DUTT1 along with tobacco addiction and nodal involvement. Our data suggests (a) ROBO1/DUTT1 and the ncRNAs are transcribed from different promoters, and (b) inactivation of ROBO1/DUTT1 could be used as molecular signature for early detection and prognosis of the head and neck cancer.
19104841	15	20	ROBO1	Gene	6091
19104841	21	26	DUTT1	Gene	6091
19104841	31	36	ROBO2	Gene	6092
19104841	282	287	ROBO1	Gene	6091
19104841	288	293	DUTT1	Gene	6091
19104841	295	300	ROBO2	Gene	6092
19104841	357	362	ROBO1	Gene	6091
19104841	363	368	DUTT1	Gene	6091
19104841	595	600	ROBO1	Gene	6091
19104841	601	606	DUTT1	Gene	6091
19104841	611	616	ROBO2	Gene	6092
19104841	652	657	ROBO1	Gene	6091
19104841	658	663	DUTT1	Gene	6091
19104841	665	670	ROBO2	Gene	6092
19104841	758	763	ROBO1	Gene	6091
19104841	764	769	DUTT1	Gene	6091
19104841	774	779	ROBO2	Gene	6092
19104841	960	965	ROBO1	Gene	6091
19104841	966	971	DUTT1	Gene	6091
19104841	977	982	ROBO2	Gene	6092
19104841	1267	1272	ROBO1	Gene	6091
19104841	1273	1278	DUTT1	Gene	6091
19104841	1283	1288	ROBO2	Gene	6092
19104841	1376	1381	ROBO1	Gene	6091
19104841	1382	1387	DUTT1	Gene	6091
19104841	1392	1397	ROBO2	Gene	6092
19104841	1540	1545	ROBO1	Gene	6091
19104841	1546	1551	DUTT1	Gene	6091
19104841	1585	1590	nodal	Gene	4838
19104841	1626	1631	ROBO1	Gene	6091
19104841	1632	1637	DUTT1	Gene	6091
19104841	1719	1724	ROBO1	Gene	6091
19104841	1725	1730	DUTT1	Gene	6091

19124645|t|Familial occurrence of schwannomas and malignant rhabdoid tumour associated with a duplication in SMARCB1.
19124645|a|BACKGROUND: The role of germline and somatic SMARCB1 gene mutations in malignant rhabdoid tumour (MRT) predisposition is well known. Germline SMARCB1 mutations have also recently been identified in a subset of individuals with schwannomatosis. Surprisingly, MRT predisposition and schwannomatosis have never been reported to co-occur in a family. The correlation between genotype and phenotype for mutations in SMARCB1 has not been determined. RESULTS: We have identified a germline 2631 bp duplication that includes exon 6 of SMARCB1 in a unique family with a four generation history of MRT predisposition and schwannomatosis. This duplication segregates with disease in individuals affected with both conditions, linking MRT predisposition and schwannomatosis as components of the same syndrome in this family. CONCLUSION: The unique combination of tumours that result from the duplication described in this report may provide important clues about the mechanisms that influence the phenotype associated with a given SMARCB1 mutation.
19124645	98	105	SMARCB1	Gene	6598
19124645	152	159	SMARCB1	Gene	6598
19124645	249	256	SMARCB1	Gene	6598
19124645	518	525	SMARCB1	Gene	6598
19124645	634	641	SMARCB1	Gene	6598
19124645	1126	1133	SMARCB1	Gene	6598

19160446|t|P2RX7: A bipolar and unipolar disorder candidate susceptibility gene?
19160446|a|The chromosomal region 12q24 has been previously implicated by linkage studies of both bipolar disorder and unipolar mood disorder and we have reported two pedigrees segregating both bipolar disorder and Darier's disease that show linkage across this region. The gene P2RX7 is located in this chromosomal region and has been recently reported as a susceptibility gene for bipolar disorder and unipolar depression. The non-synonymous SNP rs2230912 (resulting in amino-acid polymorphism Q460R) showed the strongest association and has been postulated to be pathogenically relevant. We have investigated this gene in a large UK case-control sample (bipolar I disorder N = 687, unipolar recurrent major depression N = 1,036, controls N = 1,204). Neither rs2230912 nor any of 8 other SNPs genotyped across P2RX7 was found to be associated with mood disorder in general, nor specifically with bipolar or unipolar disorder. Further, sequencing of our two chromosome 12-linked bipolar-Darier families showed no evidence of rare variants at P2RX7 that could explain the linkage. Our data do not provide support for rs2230912 or the other polymorphisms studied within the P2RX7 locus, being involved in susceptibility to mood disorders.
19160446	0	5	P2RX7	Gene	5027
19160446	338	343	P2RX7	Gene	5027
19160446	871	876	P2RX7	Gene	5027
19160446	1102	1107	P2RX7	Gene	5027
19160446	1232	1237	P2RX7	Gene	5027

19207031|t|Growth hormone dose in growth hormone-deficient adults is not associated with IGF-1 gene polymorphisms.
19207031|a|AIMS: Several SNPs and a microsatellite cytosine-adenine repeat promoter polymorphism of the IGF-1 gene have been reported to be associated with circulating IGF-1 serum concentrations. Variance in IGF-1 concentrations due to genetic variations may affect different response to growth hormone (GH) treatment, resulting in different individually required GH-doses in GH-deficient patients. The aim of this study was to test if the IGF-1 gene polymorphisms are associated with the GH-dose of GH-deficient adults. MATERIALS & METHODS: A total of nine tagging SNPs, five additionally selected SNPs and a cytosine-adenine repeat polymorphism were determined in 133 German adult patients (66 men, 67 women; mean age 45.4 years +/- 13.1 standard deviation; majority Caucasian) with GH-deficiency (GHD) of different origin, derived from the prospective Pfizer International Metabolic Study (KIMS) Pharmacogenetics Study. Patients received GH-treatment for 12 months with finished dose-titration of GH and centralized IGF-1 measurements. GH-dose after 1 year of treatment, IGF-1 concentrations, IGF-1-standard deviation score (SDS), the IGF-1:GH ratio and anthropometric data were analyzed by genotype. RESULTS: Except for rs1019731, which showed a significant difference of IGF-1-SDS by genotypes (p = 0.02), all polymorphisms showed no associations with the GH-doses, IGF-1 concentrations, IGF-1-SDS and IGF-1:GH ratio after adjusting for the confounding variables gender, age and BMI. CONCLUSION: IGF-1 gene polymorphisms were not associated with the responsiveness to exogenous GH in GHD. Therefore, genetic variations of the IGF-1 gene seem not to be major influencing factors of the GH-IGF-axis causing variable response to exogenous GH-treatment.
19207031	0	14	Growth hormone	Gene	2688
19207031	23	37	growth hormone	Gene	2688
19207031	78	83	IGF-1	Gene	3479
19207031	197	202	IGF-1	Gene	3479
19207031	261	266	IGF-1	Gene	3479
19207031	301	306	IGF-1	Gene	3479
19207031	381	395	growth hormone	Gene	2688
19207031	397	399	GH	Gene	2688
19207031	457	459	GH	Gene	2688
19207031	469	471	GH	Gene	2688
19207031	533	538	IGF-1	Gene	3479
19207031	582	584	GH	Gene	2688
19207031	593	595	GH	Gene	2688
19207031	878	880	GH	Gene	2688
19207031	1034	1036	GH	Gene	2688
19207031	1093	1095	GH	Gene	2688
19207031	1112	1117	IGF-1	Gene	3479
19207031	1132	1134	GH	Gene	2688
19207031	1167	1172	IGF-1	Gene	3479
19207031	1189	1194	IGF-1	Gene	3479
19207031	1231	1236	IGF-1	Gene	3479
19207031	1237	1239	GH	Gene	2688
19207031	1369	1374	IGF-1	Gene	3479
19207031	1454	1456	GH	Gene	2688
19207031	1464	1469	IGF-1	Gene	3479
19207031	1486	1491	IGF-1	Gene	3479
19207031	1500	1505	IGF-1	Gene	3479
19207031	1506	1508	GH	Gene	2688
19207031	1594	1599	IGF-1	Gene	3479
19207031	1676	1678	GH	Gene	2688
19207031	1724	1729	IGF-1	Gene	3479
19207031	1783	1785	GH	Gene	2688
19207031	1834	1836	GH	Gene	2688

19208385|t|Osteogenesis imperfecta type III with intracranial hemorrhage and brachydactyly associated with mutations in exon 49 of COL1A2.
19208385|a|Osteogenesis imperfecta (OI) is a heritable bone disorder characterized by fractures with minimal trauma. Intracranial hemorrhage has been reported in a small number of OI patients. Here we describe three patients, a boy (aged 15 years) and two girls (aged 17 and 7 years) with OI type III who suffered intracranial hemorrhage and in addition had brachydactyly and nail hypoplasia. In all of these patients, OI was caused by glycine mutations affecting exon 49 of the COL1A2 gene, which codes for the most carboxy-terminal part of the triple-helical domain of the collagen type I alpha 2 chain. These observations suggest that mutations in this region of the collagen type I alpha 2 chain carry a high risk of abnormal limb development and intracranial bleeding.
19208385	120	126	COL1A2	Gene	1278
19208385	596	602	COL1A2	Gene	1278
19208385	692	715	collagen type I alpha 2	Gene	1278
19208385	787	810	collagen type I alpha 2	Gene	1278

19224586|t|Quantitative PCR high-resolution melting (qPCR-HRM) curve analysis, a new approach to simultaneously screen point mutations and large rearrangements: application to MLH1 germline mutations in Lynch syndrome.
19224586|a|Several techniques have been developed to screen mismatch repair (MMR) genes for deleterious mutations. Until now, two different techniques were required to screen for both point mutations and large rearrangements. For the first time, we propose a new approach, called "quantitative PCR (qPCR) high-resolution melting (HRM) curve analysis (qPCR-HRM)," which combines qPCR and HRM to obtain a rapid and cost-effective method suitable for testing a large series of samples. We designed PCR amplicons to scan the MLH1 gene using qPCR HRM. Seventy-six patients were fully scanned in replicate, including 14 wild-type patients and 62 patients with known mutations (57 point mutations and five rearrangements). To validate the detected mutations, we used sequencing and/or hybridization on a dedicated MLH1 array-comparative genomic hybridization (array-CGH). All point mutations and rearrangements detected by denaturing high-performance liquid chromatography (dHPLC)+multiplex ligation-dependent probe amplification (MLPA) were successfully detected by qPCR HRM. Three large rearrangements were characterized with the dedicated MLH1 array-CGH. One variant was detected with qPCR HRM in a wild-type patient and was located within the reverse primer. One variant was not detected with qPCR HRM or with dHPLC due to its proximity to a T-stretch. With qPCR HRM, prescreening for point mutations and large rearrangements are performed in one tube and in one step with a single machine, without the need for any automated sequencer in the prescreening process. In replicate, its reagent cost, sensitivity, and specificity are comparable to those of dHPLC+MLPA techniques. However, qPCR HRM outperformed the other techniques in terms of its rapidity and amount of data provided.
19224586	165	169	MLH1	Gene	4292
19224586	718	722	MLH1	Gene	4292
19224586	1004	1008	MLH1	Gene	4292
19224586	1332	1336	MLH1	Gene	4292

19370769|t|SCA-LSVD: a repeat-oriented locus-specific variation database for genotype to phenotype correlations in spinocerebellar ataxias.
19370769|a|Repeat expansion has been implicated in 10 out of 17 candidate genes identified for autosomal dominant cerebellar ataxias (ADCAs)-commonly referred as spinocerebellar ataxias (SCAs). Though genetically distinct, the SCAs share a large number of features that confound their clinical classification. In addition, there is a difference in the prevalence and phenotypic expression of ataxias between different ethnic groups. We have created a new SCA-locus-specific variation database (LSVD) that aims to catalog and integrate information on SCAs associated with trinucleotide repeat expansion (SCA1, SCA 2, SCA 3, SCA 6, SCA 7, SCA 8, SCA 12, SCA 17, Friedreich's ataxia [FRDA], and dentatorubral-pallidoluysian atrophy [DRPLA]) from all over the world. The database has been developed using the Leiden Open (source) Variation Database (LOVD) software (Leiden University Medical Center, Leiden, the Netherlands). The database houses detailed information on clinical features, such as age and symptom at onset, mode of inheritance, and genotype information, pertaining to the SCA patients from more than 400 families across India. All the compiled genotype data conforms to the HGVS Nomenclature guidelines. This would be a very useful starting point for understanding the molecular correlates of phenotypes in ataxia-a multilocus disease in which related molecular mechanisms converge to overlapping phenotypes.

19450126|t|Systematic screening for polymorphisms within the UGT1A6 gene in three Chinese populations and function prediction through structural modeling.
19450126|a|AIMS: To date, there have been relatively few studies on the UGT1A6 gene in the Chinese population. The present study was designed to determine the allele frequencies and haplotypes of this gene in the population and predict the candidate functional mutations. MATERIALS & METHODS: We carried out the first systematic screening of polymorphisms of the gene in an SNP analysis involving 1074 Chinese subjects from three ethnic groups, namely Han, Dong and She, using direct sequencing. We identified the putative substrate binding pocket using a homology-modeled structure and produced a practical model for predicting the function of polymorphisms in UGT1A6. RESULTS: A total of six SNPs and 10 mutations were detected including nine known and seven novel ones. The novel mutations were 73G>A (V25I), 89T>G (L30R), 222A>C, 657C>A, 773A>T (D258V), 1040A>G (N347S) and 1467C>T. In addition, we detected, for the first time in the Chinese population, SNPs 105C>T, 627G>T as well as mutations 308C>A (S103X), IVS2+15T>C and 1088C>T (P363L). Strong linkage disequilibrium was observed among 19T>G, 315A>G, 541A>G and 552A>C. There were seven haplotypes whose frequencies were more than 0.01 in one or more of the three ethnic groups. P363L in the C-terminal domain might weaken the binding of cofactor UDPGA to the domain and induce a poor metabolism genotype of UGT1A6. CONCLUSION: Our study suggests that genetic polymorphisms in UGT1A6 may contribute to interindividual and intra-ethnic differences. The results should prove helpful in the development of pharmacogenomics in China.
19450126	50	56	UGT1A6	Gene	54578
19450126	205	211	UGT1A6	Gene	54578
19450126	795	801	UGT1A6	Gene	54578
19450126	1502	1508	UGT1A6	Gene	54578
19450126	1571	1577	UGT1A6	Gene	54578

19483196|t|Vascular endothelial growth factor gene polymorphisms as prognostic markers for ocular manifestations in pseudoxanthoma elasticum.
19483196|a|Pseudoxanthoma elasticum (PXE) is a heritable disorder affecting the skin, eyes and cardiovascular system. It is caused by mutations in the ABCC6 gene and its clinical picture is highly variable. PXE often leads to severe visual impairment due to the development of choroidal neovascularisation (CNV). CNV in PXE-associated retinopathy is believed to be mediated by the action of vascular endothelial growth factor (VEGF). The objective of the present study was to evaluate a possible impact of variations in the VEGFA gene on ocular manifestations of PXE. For this purpose, we evaluated the distribution of 10 single nucleotide polymorphisms (SNPs) in the promoter and coding region of the VEGFA gene in DNA samples from 163 German patients affected by PXE and in 163 healthy control subjects. Haplotype analysis of SNPs c.-1540A>C, c.-460C>T, c.-152G>A, c.405C>G, c.674C>T, c.1032C>T, c.4618C>T and c.5092C>A revealed that the haplotype CTGGCCCC was associated with PXE (OR 2.05, 95% CI 1.33-3.15, P(corrected) = 0.01). Furthermore, five SNPs showed significant association with severe retinopathy. The most significant single SNP association was c.-460C>T (OR 3.83, 95% CI 2.01-7.31, P(corrected) = 0.0003). Logistic regression analysis identified the c.-460T and the c.674C alleles as independent risk factors for development of severe retinopathy. Our findings suggest an involvement of VEGF in the pathogenesis of ocular PXE manifestations. VEGF gene polymorphisms might prove useful as prognostic markers for the development of PXE-associated retinopathy and permit earlier therapeutic intervention in order to prevent loss of central vision, one of the most devastating consequences of this disease.
19483196	0	34	Vascular endothelial growth factor	Gene	7422
19483196	271	276	ABCC6	Gene	368
19483196	511	545	vascular endothelial growth factor	Gene	7422
19483196	547	551	VEGF	Gene	7422
19483196	644	649	VEGFA	Gene	7422
19483196	822	827	VEGFA	Gene	7422
19483196	1523	1527	VEGF	Gene	7422
19483196	1578	1582	VEGF	Gene	7422

19508969|t|Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11).
19508969|a|BACKGROUND: Nephronophthisis (NPHP), a rare recessive cystic kidney disease, is the most frequent genetic cause of chronic renal failure in children and young adults. Mutations in nine genes (NPHP1-9) have been identified. NPHP can be associated with retinal degeneration (Senior-Løken syndrome), brainstem and cerebellar anomalies (Joubert syndrome), or liver fibrosis. METHODS: To identify a causative gene for the subset of patients with associated liver fibrosis, the authors performed a genome wide linkage search in a consanguineous family with three affected patients using 50K SNP microarrays and homozygosity mapping. RESULTS: The authors obtained a significant maximum parametric LOD (logarithm of odds) score of Z(max) = 3.72 on chromosome 8q22 and identified a homozygous missense mutation in the gene MKS3/TMEM67. When examining a worldwide cohort of 62 independent patients with NPHP and associated liver fibrosis we identified altogether four novel mutations (p.W290L, p.C615R, p.G821S, and p.G821R) in five of them. Mutations of MKS3/TMEM67, found recently in Meckel-Gruber syndrome (MKS) type 3 and Joubert syndrome (JBTS) type 6, are predominantly truncating mutations. In contrast, the mutations detected here in patients with NPHP and associated liver fibrosis are exclusively missense mutations. This suggests that they may represent hypomorphic alleles, leading to a milder phenotype compared with the more severe MKS or JBTS phenotype. Additionally, mutation analysis for MKS3/TMEM67 in 120 patients with JBTS yielded seven different (four novel) mutations in five patients, four of whom also presented with congenital liver fibrosis. CONCLUSIONS: Hypomorphic MKS3/TMEM67 mutations cause NPHP with liver fibrosis (NPHP11). This is the first report of MKS3 mutations in patients with no vermian agenesis and without neurological signs. Thus NPHP, JBTS, and MKS represent allelic disorders.
19508969	25	33	meckelin	Gene	91147
19508969	35	39	MKS3	Gene	91147
19508969	40	46	TMEM67	Gene	91147
19508969	293	298	NPHP1	Gene	4867
19508969	293	300	NPHP1-9	Gene	27130
19508969	293	300	NPHP1-9	Gene	27031
19508969	293	300	NPHP1-9	Gene	261734
19508969	293	300	NPHP1-9	Gene	9657
19508969	293	300	NPHP1-9	Gene	80184
19508969	293	300	NPHP1-9	Gene	84662
19508969	293	300	NPHP1-9	Gene	23322
19508969	293	300	NPHP1-9	Gene	284086
19508969	916	920	MKS3	Gene	91147
19508969	921	927	TMEM67	Gene	91147
19508969	1147	1151	MKS3	Gene	91147
19508969	1152	1158	TMEM67	Gene	91147
19508969	1597	1601	MKS3	Gene	91147
19508969	1602	1608	TMEM67	Gene	91147
19508969	1785	1789	MKS3	Gene	91147
19508969	1790	1796	TMEM67	Gene	91147
19508969	1876	1880	MKS3	Gene	91147

19521967|t|The role of the COMT Val(158)Met polymorphism in the phenotypic expression of obsessive-compulsive disorder.
19521967|a|Obsessive-Compulsive Disorder (OCD) is characterized by the presence of obsessions and compulsions, and shows considerable phenotypic variability. Family and twin studies have indicated a genetic component in the etiology of OCD, and the catechol-O-methyl transferase (COMT) gene is an important candidate gene for OCD. This study investigates the influence of the functional COMT Val158Met polymorphism on the phenotypic expression of OCD, using an item-level factor-analytic approach in a large sample. The COMT Val158Met variant was genotyped in 373 patients and 462 controls. It was tested whether there was an association between the COMT Val158Met polymorphism and OCD or dimensional phenotypes such as YBOCS severity score, age of onset of obsessive-compulsive symptoms and six symptom dimensions recently found in a large item-level factor-analytic study [Katerberg et al., submitted]. We further investigated possible sex-specific associations between the COMT Val158Met polymorphism and OCD or dimensional phenotypes. There was a trend for an association of the COMT 158Met allele with OCD in males, and an interaction between the COMT Val158Met genotype and sex on the somatic and sensory phenomena symptom dimension, with females showing lower scores. In conclusion, a dimensional approach seems fruitful in detecting genes of importance for OCD.
19521967	16	20	COMT	Gene	1312
19521967	29	32	Met	Gene	4233
19521967	347	376	catechol-O-methyl transferase	Gene	1312
19521967	378	382	COMT	Gene	1312
19521967	485	489	COMT	Gene	1312
19521967	618	622	COMT	Gene	1312
19521967	748	752	COMT	Gene	1312
19521967	1074	1078	COMT	Gene	1312
19521967	1181	1185	COMT	Gene	1312
19521967	1250	1254	COMT	Gene	1312

19578788|t|UVB radiation induces human lens epithelial cell migration via NADPH oxidase-mediated generation of reactive oxygen species and up-regulation of matrix metalloproteinases.
19578788|a|Ultraviolet (UV) radiation is one of the important cataract risk factors. The migration of human lens epithelial cells (HLECs) plays a crucial role in the remodeling of lens capsule and cataract formation. The purpose of the present study was to investigate the molecular mechanisms of UV-induced lens cell migration. We found that UVB radiation induces cell migration in cultured human lens epithelial cells. Further, we observed that UVB radiation induces NADPH oxidase activity and ROS generation which are inhibited by NADPH oxidase inhibitor diphenylene iodonium or DPI and antioxidant epigallocatechin gallate (EGCG). In addition, DPI and EGCG also block UVB irradiation-induced MMP-2, and -9 activity and expression and nuclear translocation of NF-kappaB. Collectively, our data suggest that NADPH oxidase may be a major source for the UVB-induced ROS generation, and it plays an essential role in the activation of NF-kappaB, which is involved in the activities of MMP-2 and MMP-9 and cell migration induced by UVB in HELCs. Understanding the cell signaling pathways may constitute potential therapeutic targets in for UVB-induced cataract.
19578788	63	76	NADPH oxidase	Gene	-1
19578788	630	643	NADPH oxidase	Gene	-1
19578788	695	708	NADPH oxidase	Gene	-1
19578788	857	862	MMP-2	Gene	4313
19578788	857	870	MMP-2, and -9	Gene	4318
19578788	924	933	NF-kappaB	Gene	4790
19578788	971	984	NADPH oxidase	Gene	-1
19578788	1095	1104	NF-kappaB	Gene	4790
19578788	1145	1150	MMP-2	Gene	4313
19578788	1155	1160	MMP-9	Gene	4318

19664744|t|A genome-wide in vitro bacterial-infection screen reveals human variation in the host response associated with inflammatory disease.
19664744|a|Recent progress in cataloguing common genetic variation has made possible genome-wide studies that are beginning to elucidate the causes and consequences of our genetic differences. Approaches that provide a mechanistic understanding of how genetic variants function to alter disease susceptibility and why they were substrates of natural selection would complement other approaches to human-genome analysis. Here we use a novel cell-based screen of bacterial infection to identify human variation in Salmonella-induced cell death. A loss-of-function allele of CARD8, a reported inhibitor of the proinflammatory protease caspase-1, was associated with increased cell death in vitro (p = 0.013). The validity of this association was demonstrated through overexpression of alternative alleles and RNA interference in cells of varying genotype. Comparison of mammalian CARD8 orthologs and examination of variation among different human populations suggest that the increase in infectious-disease burden associated with larger animal groups (i.e., herds and colonies), and possibly human population expansion, may have naturally selected for loss of CARD8. We also find that the loss-of-function CARD8 allele shows a modest association with an increased risk of systemic inflammatory response syndrome in a small study (p = 0.05). Therefore, a by-product of the selected benefit of loss of CARD8 could be increased inflammatory diseases. These results demonstrate the utility of genome-wide cell-based association screens with microbes in the identification of naturally selected variants that can impact human health.
19664744	694	699	CARD8	Gene	22900
19664744	754	763	caspase-1	Gene	834
19664744	999	1004	CARD8	Gene	22900
19664744	1279	1284	CARD8	Gene	-1
19664744	1325	1330	CARD8	Gene	22900
19664744	1519	1524	CARD8	Gene	22900

19696792|t|Single nucleotide polymorphism in ABCG2 is associated with irinotecan-induced severe myelosuppression.
19696792|a|Irinotecan is an anti-neoplastic agent that is widely used for treating colorectal and lung cancers, but often causes toxicities such as severe myelosuppression and diarrhea. In this study, we performed a two-stage case-control association study for irinotecan-induced severe myelosuppression (grades 3 and 4). In the first stage, 23 patients who developed severe myelosuppression and 58 patients who did not develop any toxicity were examined for 170 single nucleotide polymorphisms (SNPs) in 14 genes involved in the metabolism and transport of irinotecan. A total of five SNPs were identified to show the possible association with severe myelosuppression (P(Fisher)<0.01) and were further examined in 7 cases and 20 controls in the second stage of the study. An intronic SNP, rs2622604, in ABCG2 showed P(Fisher)=0.0419 in the second stage and indicated a significant association with severe myelosuppression in the combined study (P(Fisher)=0.000237; P(Corrected)=0.036). Although only limited subjects were investigated, our results suggested that a genetic polymorphism in ABCG2 might alter the transport activity for the drug and elevate the systemic circulation level of irinotecan, leading to severe myelosuppression.
19696792	34	39	ABCG2	Gene	9429
19696792	896	901	ABCG2	Gene	9429
19696792	1182	1187	ABCG2	Gene	9429

19779499|t|Novel CACNA1S mutation causes autosomal dominant hypokalemic periodic paralysis in a South American family.
19779499|a|Hypokalaemic periodic paralysis (HypoPP) is an autosomal dominant disorder, which is characterized by periodic attacks of muscle weakness associated with a decrease in the serum potassium level. A major disease-causing gene for HypoPP has been identified as CACNA1S, which encodes the skeletal muscle calcium channel alpha-subunit with four transmembrane domains (I-IV), each with six transmembrane segments (S1-S6). To date, all CACNA1S mutations identified in HypoPP patients are located within the voltage-sensor S4 segment. In this study we report a novel CACNA1S mutation in a new region of the protein, the S3 segment of domain III. We characterized a four-generation South American family with HypoPP. Genetic analysis identified a novel V876E mutation in all HypoPP patients in the family, but not in normal family members or 160 control people. Clinical analysis indicates that mutation V876E is associated with a severe outcome as characterized by a very early age of onset, complete penetrance and a severe prognosis including death. These results identify a new mutation in CACNA1S and expand the spectrum of CACNA1S mutations associated with HypoPP.
19779499	6	13	CACNA1S	Gene	779
19779499	366	373	CACNA1S	Gene	779
19779499	538	545	CACNA1S	Gene	779
19779499	668	675	CACNA1S	Gene	779
19779499	1194	1201	CACNA1S	Gene	779
19779499	1229	1236	CACNA1S	Gene	779

19891556|t|Clopidogrel pharmacogenomics and risk of inadequate platelet inhibition: US FDA recommendations.
19891556|a|Antiplatelet therapy with clopidogrel is the current standard of care for coronary artery disease patients undergoing a percutaneous coronary intervention. However, approximately 25% of patients experience a subtherapeutic antiplatelet response. Clopidogrel is a prodrug that undergoes hepatic biotransformation by CYP2C19 into its active metabolite. Several studies have reported that, compared with wild-type individuals, CYP2C19 variant allele carriers exhibit a significantly lower capacity to metabolize clopidogrel into its active metabolite and inhibit platelet activation, and are therefore at significantly higher risk of adverse cardiovascular events. Consequently, the US FDA has recently changed clopidogrel's prescribing information to highlight the impact of CYP2C19 genotype on clopidogrel pharmacokinetics, pharmacodynamics and clinical response. Future studies remain necessary to develop effective personalized therapeutic strategies for CYP2C19 variant allele carriers and other individuals at risk for clopidogrel nonresponsiveness.
19891556	412	419	CYP2C19	Gene	1557
19891556	521	528	CYP2C19	Gene	1557
19891556	870	877	CYP2C19	Gene	1557
19891556	1053	1060	CYP2C19	Gene	1557

19896957|t|DNA fragmentation in human fibroblasts under extremely low frequency electromagnetic field exposure.
19896957|a|Extremely low frequency electromagnetic fields (ELF-EMFs) were reported to affect DNA integrity in human cells with evidence based on the Comet assay. These findings were heavily debated for two main reasons; the lack of reproducibility, and the absence of a plausible scientific rationale for how EMFs could damage DNA. Starting out from a replication of the relevant experiments, we performed this study to clarify the existence and explore origin and nature of ELF-EMF induced DNA effects. Our data confirm that intermittent (but not continuous) exposure of human primary fibroblasts to a 50 Hz EMF at a flux density of 1 mT induces a slight but significant increase of DNA fragmentation in the Comet assay, and we provide first evidence for this to be caused by the magnetic rather than the electric field. Moreover, we show that EMF-induced responses in the Comet assay are dependent on cell proliferation, suggesting that processes of DNA replication rather than the DNA itself may be affected. Consistently, the Comet effects correlated with a reduction of actively replicating cells and a concomitant increase of apoptotic cells in exposed cultures, whereas a combined Fpg-Comet test failed to produce evidence for a notable contribution of oxidative DNA base damage. Hence, ELF-EMF induced effects in the Comet assay are reproducible under specific conditions and can be explained by minor disturbances in S-phase processes and occasional triggering of apoptosis rather than by the generation of DNA damage.

19953639|t|Molecular and clinical heterogeneity in CLCN7-dependent osteopetrosis: report of 20 novel mutations.
19953639|a|The "Osteopetroses" are genetic diseases whose clinical picture is caused by a defect in bone resorption by osteoclasts. Three main forms can be distinguished on the basis of severity, age of onset and means of inheritance: the dominant benign, the intermediate and the recessive severe form. While several genes have been involved in the pathogenesis of the different types of osteopetroses, the CLCN7 gene has drawn the attention of many researchers, as mutations within this gene are associated with very different phenotypes. We report here the characterization of 25 unpublished patients which has resulted in the identification of 20 novel mutations, including 11 missense mutations, 6 causing premature termination, 1 small deletion and 2 putative splice site defects. Careful analysis of clinical and molecular data led us to several conclusions. First, intermediate osteopetrosis is not homogeneous, since it can comprise both severe dominant forms with an early onset and recessive ones without central nervous system involvement. Second, the appropriateness of haematopoietic stem cell transplantation in CLCN7-dependent ARO patients has to be carefully evaluated and exhaustive CNS examination is strongly suggested, as transplantation can almost completely cure the disease in situations where no primary neurological symptoms are present. Finally, the analysis of this largest cohort of CLCN7-dependent ARO patients together with some ADO II families allowed us to draw preliminary genotype-phenotype correlations suggesting that haploinsufficiency is not the mechanism causing ADO II. The availability of biochemical assays to characterize ClC-7 function will help to confirm this hypothesis.
19953639	40	45	CLCN7	Gene	1186
19953639	498	503	CLCN7	Gene	1186
19953639	1217	1222	CLCN7	Gene	1186
19953639	1502	1507	CLCN7	Gene	1186
19953639	1756	1761	ClC-7	Gene	1186

20031581|t|Association and functional analyses of MEF2A as a susceptibility gene for premature myocardial infarction and coronary artery disease.
20031581|a|BACKGROUND: Mutations in the MEF2A gene, coding for a member of the myocyte enhancer factor 2 family of transcription factors, have been reported in patients with coronary artery disease and myocardial infarction (MI). In particular, a 21-bp deletion and 3 missense mutations were demonstrated either to reduce MEF2A transcriptional activity or to impair its nuclear translocation. However, the association of MEF2A with coronary artery disease/MI was not confirmed in other studies. We analyzed the role of MEF2A in the pathogenesis of MI in 2008 Italian patients with premature MI and in 2008 controls. METHODS AND RESULTS: Mutational screening of exon 8 (containing all so-far reported point mutations) disclosed 5 novel and 2 previously described missense mutations. Microsatellite genotyping and sequencing revealed the presence of the 21-bp deletion (located in exon 12) in 5 cases and in none of the controls. Functional studies on mutant proteins showed no alteration, neither in the transactivating properties (all mutants) nor in the nuclear localization (21-bp deletion). Furthermore, an association analysis performed using 3 microsatellites at the MEF2A locus showed no significant association with MI. These results were confirmed in a replication study performed on an independent Italian population with coronary artery disease. CONCLUSIONS: All together, our data do not support MEF2A as a susceptibility gene for coronary artery disease/MI in the Italian population.
20031581	39	44	MEF2A	Gene	4205
20031581	164	169	MEF2A	Gene	4205
20031581	446	451	MEF2A	Gene	4205
20031581	545	550	MEF2A	Gene	4205
20031581	643	648	MEF2A	Gene	4205
20031581	1296	1301	MEF2A	Gene	4205
20031581	1531	1536	MEF2A	Gene	4205

20132244|t|Novel and recurrent p14 mutations in Italian familial melanoma.
20132244|a|CDKN2A and CDK4 are the only known high-penetrant genes conferring proneness to cutaneous melanoma. The CDKN2A locus consists of four exons and encodes several alternate transcripts, two of which are p16(INK4a) and p14(ARF), and originate from different open reading frames. Exon 1alpha is specific for p16(INK4a), while exon 1beta characterizes p14(ARF). Most CDKN2A mutations are located in exons 1alpha and 2, while exon 1beta variations have been identified in rare melanoma-prone pedigrees. In a previous study, we investigated 155 Italian melanoma cases, including 94 familial melanomas (FAMs) and 61 sporadic multiple primary melanomas (MPMs), for p16(INK4a)/CDK4 germline alterations and identified 15 p16(INK4a) and 1 CDK4 point mutations. In the present work, we extended our search to p14(ARF) mutations and CDKN2A deletions in the remaining samples. We identified the recurrent g.193+1G> A mutation in two FAM cases, while an additional pedigree displayed the previously undescribed variant g.161G> A. Multiplex ligation-dependent probe amplification (MLPA) screening for copy variations resulted negative in all cases. In Italy, the overall frequency of p14(ARF) mutations is 3.2% in FAM and 0% in sporadic MPM. Re-evaluation of our patients' cohort emphasizes that the chance of identifying CDKN2A/CDK4 mutations in FAM is mainly influenced by the number of affected family members and the presence of one or more MPM cases. Accordingly, mutation rate rises to 61% in selected cases. Further studies are expected in order to investigate CDKN2A rarer mutations, including atypical deletions and inherited epimutations.
20132244	20	23	p14	Gene	1029
20132244	64	70	CDKN2A	Gene	1029
20132244	75	79	CDK4	Gene	1019
20132244	168	174	CDKN2A	Gene	1029
20132244	264	267	p16	Gene	1029
20132244	268	273	INK4a	Gene	1029
20132244	279	282	p14	Gene	1029
20132244	283	286	ARF	Gene	1029
20132244	367	370	p16	Gene	1029
20132244	371	376	INK4a	Gene	1029
20132244	410	413	p14	Gene	1029
20132244	414	417	ARF	Gene	1029
20132244	425	431	CDKN2A	Gene	1029
20132244	719	722	p16	Gene	1029
20132244	723	728	INK4a	Gene	1029
20132244	730	734	CDK4	Gene	1019
20132244	774	777	p16	Gene	1029
20132244	778	783	INK4a	Gene	1029
20132244	791	795	CDK4	Gene	1019
20132244	860	863	p14	Gene	1029
20132244	864	867	ARF	Gene	1029
20132244	883	889	CDKN2A	Gene	1029
20132244	1231	1234	p14	Gene	1029
20132244	1235	1238	ARF	Gene	1029
20132244	1369	1375	CDKN2A	Gene	1029
20132244	1376	1380	CDK4	Gene	1019
20132244	1615	1621	CDKN2A	Gene	1029

20186809|t|Intellectual disability, midface hypoplasia, facial hypotonia, and Alport syndrome are associated with a deletion in Xq22.3.
20186809|a|Alport syndrome with intellectual disability (ID) is a contiguous gene deletion syndrome involving several genes on Xq22.3 including COL4A5 and ACSL4. We report on a family with two males with this disorder and a Xq22.3 deletion. Fluorescent in situ hybridization and genomic analyses mapped the deletion region to between exon 1 of COL4A5 and exon 12 of ACSL4. The patients' mother has microscopic hematuria and was found to be heterozygous for the Xq22.3 deletion. Analysis using reverse transcription polymerase chain reaction of lymphoblastoid cell line RNA from an affected male in the family revealed a stable chimeric transcript with the ACSL4 exons 13-17 replaced by a cryptic exon from intron 1 of the COL4A5 gene. A truncated 54 kDa protein was predicted from this transcript but Western blot analysis and ACSL4 enzyme assay both showed functional nullisomy of ACSL4. We also compared the clinical features of the family with three previously reported families with the ACSL4 gene deletion and found that ID with absent or severely delayed speech, midface hypoplasia, and facial hypotonia are consistent features observed in the absence of ACSL4 gene.
20186809	258	264	COL4A5	Gene	1287
20186809	269	274	ACSL4	Gene	2182
20186809	458	464	COL4A5	Gene	1287
20186809	480	485	ACSL4	Gene	2182
20186809	770	775	ACSL4	Gene	2182
20186809	836	842	COL4A5	Gene	1287
20186809	941	946	ACSL4	Gene	2182
20186809	996	1001	ACSL4	Gene	2182
20186809	1105	1110	ACSL4	Gene	2182
20186809	1275	1280	ACSL4	Gene	2182

20195899|t|Potential liability of reproductive endocrinologists for high order multiple gestation.
20195899|a|BACKGROUND: In light of the recent octuplet birth and the accompanying intensive media coverage, there has been much attention on high order multiple births resulting from assisted reproductive technology. OBJECTIVES: The purpose of this commentary is to review 1) the relative contribution of ART to high order multiple gestation and its impact on infant morbidity, mortality, and health care dollar loss; 2) American Society of Reproductive Medicine's guidelines for the number of embryos transferred in ART; and 3) how reproductive endocrinologists can lessen their exposure to litigation by following the ASRM guidelines for the number of embryos transferred and documenting proper informed consent in the medical records. RECOMMENDATIONS: In situations in which the number of embryos transferred is in excess of the ASRM guidelines, justification for deviating from the ASRM guidelines should be justifiable and documented in the medical records.

20401977|t|The human AHR: identification of single nucleotide polymorphisms from six ethnic populations.
20401977|a|BACKGROUND: The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related dioxin-like chemicals are mediated through binding-dependent activation of the cytosolic aryl hydrocarbon receptor (AHR). The human AHR is a low-affinity receptor relative to most rodents, but some reports suggest that there may be individuals with polymorphic high-affinity receptors, thereby possibly increasing the sensitivity to dioxins in such people. METHODS: Although no polymorphisms have been reported in the ligand binding region of the AHR in the over 100 reported sequences, we sequenced 108 additional human AHR genes in an effort to further identify single single nucleotide polymorphisms (SNPs) within the open reading frames of the AHR locus. The DNA was sequenced from six ethnic populations that included Japanese, Chinese, European/Caucasian, African-American, South East Asian, and Hispanic. RESULTS: Six exonic SNPs were identified; four had been described as previously reported and two seem to be novel. Four of the SNPs identified lead to amino acid changes in the AHR protein and two of the SNPs lead to synonymous substitutions. An additional four SNPs have been reported elsewhere that were not identified in the current analysis. With these new sequences, more than 200 human AHR gene sequences have been analyzed for SNPs. CONCLUSION: The results indicate a very limited presence of polymorphisms in the core ligand binding region of the human AHR. Other regions, such as the transactivation domain, seem to be slightly more polymorphic in the human population and the impact on functionality should be further examined.
20401977	10	13	AHR	Gene	196
20401977	258	283	aryl hydrocarbon receptor	Gene	196
20401977	285	288	AHR	Gene	196
20401977	301	304	AHR	Gene	196
20401977	616	619	AHR	Gene	196
20401977	690	693	AHR	Gene	196
20401977	817	820	AHR	Gene	196
20401977	1158	1161	AHR	Gene	196
20401977	1373	1376	AHR	Gene	196
20401977	1542	1545	AHR	Gene	196

20415560|t|Vitamin E reduces cardiovascular disease in individuals with diabetes mellitus and the haptoglobin 2-2 genotype.
20415560|a|AIMS: Individuals with both diabetes mellitus (DM) and the Haptoglobin (Hp) 2-2 genotype are at increased risk of cardiovascular disease. As the antioxidant function of the Hp 2-2 protein is impaired, we sought to test the pharmacogenomic hypothesis that antioxidant vitamin E supplementation would provide cardiovascular protection to Hp 2-2 DM individuals. MATERIALS & METHODS: We determined the Hp genotype on DM participants from two trials (HOPE and ICARE) and assessed the effect of vitamin E by Hp genotype on their common prespecified outcome, the composite of stroke, myocardial infarction and cardiovascular death. Data was analyzed with a fixed-effect model. These results were input into a simulation model, the Evidence Based Medicine Integrator, in order to estimate their long-term implications in a real-world population from Kaiser Permanente (CA, USA). RESULTS: Meta-analysis of the two trials demonstrated a significant overall reduction in the composite end point in Hp 2-2 DM individuals with vitamin E (odds ratio: 0.58; 95% CI: 0.40-0.86; p = 0.006). There was a statistically significant interaction between the Hp genotype and vitamin E on the composite end point. In these trials, Hp typing of 69 DM individuals and treating those with the Hp 2-2 with vitamin E prevented one myocardial infarct, stroke or cardiovascular death. Lifelong administration of vitamin E to Hp 2-2 DM individuals in the Kaiser population would increase their life expectancy by 3 years. CONCLUSION: A pharmacogenomic strategy of screening DM individuals for the Hp genotype and treating those with Hp 2-2 with vitamin E appears to be highly clinically effective.
20415560	87	98	haptoglobin	Gene	3240
20415560	172	183	Haptoglobin	Gene	3240
20415560	185	187	Hp	Gene	3240
20415560	286	288	Hp	Gene	3240
20415560	449	451	Hp	Gene	3240
20415560	511	513	Hp	Gene	3240
20415560	615	617	Hp	Gene	3240
20415560	1100	1102	Hp	Gene	3240
20415560	1249	1251	Hp	Gene	3240
20415560	1320	1322	Hp	Gene	3240
20415560	1379	1381	Hp	Gene	3240
20415560	1507	1509	Hp	Gene	3240
20415560	1678	1680	Hp	Gene	3240
20415560	1714	1716	Hp	Gene	3240

20428796|t|Effect of the abrogation of TGF-beta1 by antisense oligonucleotides on the expression of TGF-beta-isoforms and their receptors I and II in isolated fibroblasts from keloid scars.
20428796|a|Disequilibrium of dermal wound repair can result in continued accumulation of ECM and excessive scar formation. In susceptible genetically predisposed individuals, keloid formation can be observed. Keloid disease represents a benign dermal fibroproliferative tumor that is unique to humans. TGF-beta is known to play a key role in the pathogenesis of this disease which is still not fully understood. The isoforms TGF-beta1 and TGF-beta2 have profibrotic properties, whereas TGF-beta3 may have antifibrotic functions. TGF-beta exerts its influence by binding to type I and type II TGF-beta receptors, thereby forming a complex and activating specific downstream effector molecules. The aim of this study was to investigate the effect of TGF-beta1 targeting by antisense oligonucleotides on the RNA synthesis and protein expression of TGF-beta isoforms and their receptors in keloid-derived fibroblasts. In tissue samples with normal fibroblasts (NFs) serving as control samples, expression of TGF-beta1 and -beta2 was decreased when compared to keloid fibroblasts (KFs), while expression of TGF-beta3 and of TGF-betaRII was significantly higher in NFs. In the ELISA assay, abrogation of TGF-beta1 led to a significant decrease in TGF-beta1 and -beta2 (p<0.05). Expression of TGF-beta2 mRNA was reduced. Expression of TGF-beta3 mRNA revealed contrary patterns in KFs from different patients while expression of TGF-betaRI was found to be equal during the measurement period. TGF-betaRII mRNA expression was increased after 48 and 72 h respectively. There is growing evidence for a regulatory mechanism between TGF-beta1 and its receptors. Our findings support this theory by suggesting interrelations between the different TGF-beta isoforms and their receptors. Abnormal response of KFs to TGF-betamight reflect a modification in the regulatory pathway that occurs at the receptor level or during intracellular trans-duction. Improving the understanding of TGF-beta in keloid disease could lead to the development of clinically useful therapeutic modalities for treatment of keloid disease or even allow identification of preventive strategies.
20428796	28	37	TGF-beta1	Gene	4052
20428796	89	135	TGF-beta-isoforms and their receptors I and II	Gene	7046
20428796	89	135	TGF-beta-isoforms and their receptors I and II	Gene	7048
20428796	593	602	TGF-beta1	Gene	4052
20428796	607	616	TGF-beta2	Gene	7042
20428796	654	663	TGF-beta3	Gene	7043
20428796	741	778	type I and type II TGF-beta receptors	Gene	7046
20428796	741	778	type I and type II TGF-beta receptors	Gene	7048
20428796	916	925	TGF-beta1	Gene	4052
20428796	1172	1192	TGF-beta1 and -beta2	Gene	4052
20428796	1172	1192	TGF-beta1 and -beta2	Gene	7042
20428796	1270	1279	TGF-beta3	Gene	7043
20428796	1366	1375	TGF-beta1	Gene	4052
20428796	1409	1429	TGF-beta1 and -beta2	Gene	4052
20428796	1409	1429	TGF-beta1 and -beta2	Gene	7042
20428796	1454	1463	TGF-beta2	Gene	7042
20428796	1496	1505	TGF-beta3	Gene	7043
20428796	1589	1599	TGF-betaRI	Gene	7046
20428796	1653	1664	TGF-betaRII	Gene	7048
20428796	1788	1797	TGF-beta1	Gene	4052

20513137|t|NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype.
20513137|a|In 5-10% of patients, neurofibromatosis type 1 (NF1) results from microdeletions that encompass the entire NF1 gene and a variable number of flanking genes. Two recurrent microdeletion types are found in most cases, with microdeletion breakpoints located in paralogous regions flanking NF1 (proximal NF1-REP-a and distal NF1-REP-c for the 1.4 Mb type-1 microdeletion, and SUZ12 and SUZ12P for the 1.2 Mb type-2 microdeletion). A more severe phenotype is usually associated with NF1 microdeletion patients than in those with intragenic mutations. We characterized NF1 microdeletions in 70 unrelated NF1 microdeleted patients using a high-resolution NF1 custom array comparative genomic hybridization (CGH). Genotype-phenotype correlations were studied in 58 of these microdeletion patients and compared to 389 patients with intragenic truncating NF1 mutations and phenotyped in the same standardized way. Our results confirmed in an unbiased manner the existence of a contiguous gene syndrome with a significantly higher incidence of learning disabilities and facial dysmorphism in microdeleted patients compared to patients with intragenic NF1 mutations. Microdeleted NF1 patients also showed a trend toward significance for childhood overgrowth. High-resolution array-CGH identified a new recurrent approximately 1.0 Mb microdeletion type, designated as type-3, with breakpoints in the paralogous regions middle NF1-REP-b and distal NF1-REP-c.
20513137	0	3	NF1	Gene	4763
20513137	183	186	NF1	Gene	4763
20513137	362	365	NF1	Gene	4763
20513137	376	379	NF1	Gene	4763
20513137	397	400	NF1	Gene	4763
20513137	448	453	SUZ12	Gene	23512
20513137	458	464	SUZ12P	Gene	440423
20513137	554	557	NF1	Gene	4763
20513137	639	642	NF1	Gene	4763
20513137	674	677	NF1	Gene	4763
20513137	724	727	NF1	Gene	4763
20513137	921	924	NF1	Gene	4763
20513137	1216	1219	NF1	Gene	4763
20513137	1244	1247	NF1	Gene	4763
20513137	1489	1492	NF1	Gene	4763
20513137	1510	1513	NF1	Gene	4763

20540798|t|Sex-differential genetic effect of phosphodiesterase 4D (PDE4D) on carotid atherosclerosis.
20540798|a|BACKGROUND: The phosphodiesterase 4D (PDE4D) gene was reported as a susceptibility gene to stroke. The genetic effect might be attributed to its role in modulating the atherogenic process in the carotid arteries. Using carotid intima-media thickness (IMT) and plaque index as phenotypes, the present study sought to determine the influence of this gene on subclinical atherosclerosis. METHODS: Carotid ultrasonography was performed on 1013 stroke-free subjects who participated in the health screening programs (age 52.6 +/- 12.2; 47.6% men). Genotype distribution was compared among the high-risk (plaque index > or = 4), low-risk (index = 1-3), and reference (index = 0) groups. We analyzed continuous IMT data and further dichotomized IMT data using mean plus one standard deviation as the cutoff level. Because the plaque prevalence and IMT values displayed a notable difference between men and women, we carried out sex-specific analyses in addition to analyzing the overall data. Rs702553 at the PDE4D gene was selected because it conferred a risk for young stroke in our previous report. Previous young stroke data (190 cases and 211 controls) with an additional 532 control subjects without ultrasonic data were shown as a cross-validation for the genetic effect. RESULTS: In the overall analyses, the rare homozygote of rs702553 led to an OR of 3.1 (p = 0.034) for a plaque index > or = 4. When subjects were stratified by sex, the genetic effect was only evident in men but not in women. Comparing male subjects with plaque index > or = 4 and those with plaque index = 0, the TT genotype was over-represented (27.6% vs. 13.4%, p = 0.008). For dichotomized IMT data in men, the TT genotype had an OR of 2.1 (p = 0.032) for a thicker IMT at the common carotid artery compared with the (AA + AT) genotypes. In women, neither IMT nor plaque index was associated with rs702553. Similarly, SNP rs702553 was only significant in young stroke men (OR = 1.8, p = 0.025) but not in women (p = 0.27). CONCLUSIONS: The present study demonstrates a sex-differential effect of PDE4D on IMT, plaque index and stroke, which highlights its influence on various aspects of atherogenesis.
20540798	35	55	phosphodiesterase 4D	Gene	5144
20540798	57	62	PDE4D	Gene	5144
20540798	108	128	phosphodiesterase 4D	Gene	5144
20540798	130	135	PDE4D	Gene	5144
20540798	1094	1099	PDE4D	Gene	5144
20540798	2164	2169	PDE4D	Gene	5144

20596603|t|Identification of lipid droplet-associated proteins in the formation of macrophage-derived foam cells using microarrays.
20596603|a|A large number of macrophage-derived foam cells stores excessive neutral lipids in intracellular droplets, and plays a major role during the development of atherosclerosis. The formation and catabolism of intracellular lipid droplets (LDs) are regulated by LD-associated proteins, a group of proteins which are located on the surface of LDs and regulate the formation, morphology and lipolysis of LDs. In order to illustrate the function of LD-associated proteins during the process of atherosclerosis, the foam cell model is induced by oxidized low-density lipoprotein (ox-LDL) in macrophages originated from the THP-1 cell line, and cDNA microarrays are used to monitor the gene expression profiles of LD-associated proteins. Gene expression data show that 2% of changed genes are lipid binding genes during the transformation of foam cells. The major candidate genes, the cell death-inducing DFF45-like effector (CIDE) family and Perilipin, Adipophilin, and TIP47 (PAT) family, have different alterations during the formation of foam cells. CIDEB, CIDEC, Adipophilin, S3-12 and LSDP5 were up-regulated, while TIP47 was down-regulated. There was no significant change in CIDEA and Perilipin. These results were confirmed by real-time PCR and immunoblotting. This study presents a comprehensive analysis of the gene expression of LD-associated proteins during the differentiation of human foam cells, which may play an important role in the process of atherosclerosis.
20596603	1054	1063	Perilipin	Gene	5346
20596603	1065	1076	Adipophilin	Gene	123
20596603	1082	1087	TIP47	Gene	10226
20596603	1089	1092	PAT	Gene	5346
20596603	1089	1092	PAT	Gene	123
20596603	1089	1092	PAT	Gene	10226
20596603	1165	1170	CIDEB	Gene	27141
20596603	1172	1177	CIDEC	Gene	63924
20596603	1179	1190	Adipophilin	Gene	123
20596603	1192	1197	S3-12	Gene	729359
20596603	1202	1207	LSDP5	Gene	440503
20596603	1233	1238	TIP47	Gene	10226
20596603	1294	1299	CIDEA	Gene	1149
20596603	1304	1313	Perilipin	Gene	5346

20663204|t|Genomic characterization of large rearrangements of the LDLR gene in Czech patients with familial hypercholesterolemia.
20663204|a|BACKGROUND: Mutations in the LDLR gene are the most frequent cause of Familial hypercholesterolemia, an autosomal dominant disease characterised by elevated concentrations of LDL in blood plasma. In many populations, large genomic rearrangements account for approximately 10% of mutations in the LDLR gene. METHODS: DNA diagnostics of large genomic rearrangements was based on Multiple Ligation dependent Probe Amplification (MLPA). Subsequent analyses of deletion and duplication breakpoints were performed using long-range PCR, PCR, and DNA sequencing. RESULTS: In set of 1441 unrelated FH patients, large genomic rearrangements were found in 37 probands. Eight different types of rearrangements were detected, from them 6 types were novel, not described so far. In all rearrangements, we characterized their exact extent and breakpoint sequences. CONCLUSIONS: Sequence analysis of deletion and duplication breakpoints indicates that intrachromatid non-allelic homologous recombination (NAHR) between Alu elements is involved in 6 events, while a non-homologous end joining (NHEJ) is implicated in 2 rearrangements. Our study thus describes for the first time NHEJ as a mechanism involved in genomic rearrangements in the LDLR gene.
20663204	56	60	LDLR	Gene	3949
20663204	149	153	LDLR	Gene	3949
20663204	416	420	LDLR	Gene	3949
20663204	1344	1348	LDLR	Gene	3949

20691404|t|Loss of corneodesmosin leads to severe skin barrier defect, pruritus, and atopy: unraveling the peeling skin disease.
20691404|a|Generalized peeling skin disease is an autosomal-recessive ichthyosiform erythroderma characterized by lifelong patchy peeling of the skin. After genome-wide linkage analysis, we have identified a homozygous nonsense mutation in CDSN in a large consanguineous family with generalized peeling skin, pruritus, and food allergies, which leads to a complete loss of corneodesmosin. In contrast to hypotrichosis simplex, which can be associated with specific dominant CDSN mutations, peeling skin disease is characterized by a complete loss of CDSN expression. The skin phenotype is consistent with a recent murine Cdsn knockout model. Using three-dimensional human skin models, we demonstrate that lack of corneodesmosin causes an epidermal barrier defect supposed to account for the predisposition to atopic diseases, and we confirm the role of corneodesmosin as a decisive epidermal adhesion molecule. Therefore, peeling skin disease will represent a new model disorder for atopic diseases, similarly to Netherton syndrome and ichthyosis vulgaris in the recent past.
20691404	8	22	corneodesmosin	Gene	1041
20691404	347	351	CDSN	Gene	1041
20691404	480	494	corneodesmosin	Gene	1041
20691404	581	585	CDSN	Gene	1041
20691404	657	661	CDSN	Gene	1041
20691404	728	732	Cdsn	Gene	1041
20691404	820	834	corneodesmosin	Gene	1041
20691404	960	974	corneodesmosin	Gene	1041