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0 | 22016685 | [
{
"id": "5",
"type": "title",
"text": [
"A novel missense mutation Asp506Gly in Exon 13 of the F11 gene in an asymptomatic Korean woman with mild factor XI deficiency."
],
"offsets": [
[
0,
126
]
]
},
{
"id": "6",
"type": "abstract",
"text": [
"Factor XI (FXI) deficiency is a rare autosomal recessive coagulation disorder most commonly found in Ashkenazi and Iraqi Jews, but it is also found in other ethnic groups. It is a trauma or surgery-related bleeding disorder, but spontaneous bleeding is rarely seen. The clinical manifestation of bleeding in FXI deficiency cases is variable and seems to poorly correlate with plasma FXI levels. The molecular pathology of FXI deficiency is mutation in the F11 gene on the chromosome band 4q35. We report a novel mutation of the F11 gene in an 18-year-old asymptomatic Korean woman with mild FXI deficiency. Pre-operative laboratory screen tests for lipoma on her back revealed slightly prolonged activated partial thromboplastin time (45.2 sec; reference range, 23.2-39.4 sec). Her FXI activity (35%) was slightly lower than the normal FXI activity (reference range, 50-150%). Direct sequence analysis of the F11 gene revealed a heterozygous A to G substitution in nucleotide 1517 (c.1517A>G) of exon 13, resulting in the substitution of aspartic acid with glycine in codon 506 (p.Asp506Gly). To the best of our knowledge, the Asp506Gly is a novel missense mutation, and this is the first genetically confirmed case of mild FXI deficiency in Korea."
],
"offsets": [
[
127,
1375
]
]
}
] | [
{
"id": "1",
"type": "ProteinMutation",
"text": [
"Asp506Gly"
],
"offsets": [
[
26,
35
]
],
"normalized": []
},
{
"id": "2",
"type": "DNAMutation",
"text": [
"c.1517A>G"
],
"offsets": [
[
1109,
1118
]
],
"normalized": []
},
{
"id": "3",
"type": "ProteinMutation",
"text": [
"p.Asp506Gly"
],
"offsets": [
[
1206,
1217
]
],
"normalized": []
},
{
"id": "4",
"type": "ProteinMutation",
"text": [
"Asp506Gly"
],
"offsets": [
[
1254,
1263
]
],
"normalized": []
}
] | [] | [] | [] |
7 | 21850008 | [
{
"id": "18",
"type": "title",
"text": [
"Mutations in mitochondrially encoded complex I enzyme as the second common cause in a cohort of Chinese patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes."
],
"offsets": [
[
0,
199
]
]
},
{
"id": "19",
"type": "abstract",
"text": [
"The mutation pattern of mitochondrial DNA (mtDNA) in mainland Chinese patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) has been rarely reported, though previous data suggested that the mutation pattern of MELAS could be different among geographically localized populations. We presented the results of comprehensive mtDNA mutation analysis in 92 unrelated Chinese patients with MELAS (85 with classic MELAS and 7 with MELAS/Leigh syndrome (LS) overlap syndrome). The mtDNA A3243G mutation was the most common causal genotype in this patient group (79/92 and 85.9%). The second common gene mutation was G13513A (7/92 and 7.6%). Additionally, we identified T10191C (p.S45P) in ND3, A11470C (p. K237N) in ND4, T13046C (p.M237T) in ND5 and a large-scale deletion (13025-13033:14417-14425) involving partial ND5 and ND6 subunits of complex I in one patient each. Among them, A11470C, T13046C and the single deletion were novel mutations. In summary, patients with mutations affecting mitochondrially encoded complex I (MTND) reached 12.0% (11/92) in this group. It is noteworthy that all seven patients with MELAS/LS overlap syndrome were associated with MTND mutations. Our data emphasize the important role of MTND mutations in the pathogenicity of MELAS, especially MELAS/LS overlap syndrome."
],
"offsets": [
[
200,
1544
]
]
}
] | [
{
"id": "8",
"type": "DNAMutation",
"text": [
"A3243G"
],
"offsets": [
[
727,
733
]
],
"normalized": []
},
{
"id": "9",
"type": "DNAMutation",
"text": [
"G13513A"
],
"offsets": [
[
856,
863
]
],
"normalized": []
},
{
"id": "10",
"type": "DNAMutation",
"text": [
"T10191C"
],
"offsets": [
[
909,
916
]
],
"normalized": []
},
{
"id": "11",
"type": "ProteinMutation",
"text": [
"p.S45P"
],
"offsets": [
[
918,
924
]
],
"normalized": []
},
{
"id": "12",
"type": "DNAMutation",
"text": [
"A11470C"
],
"offsets": [
[
934,
941
]
],
"normalized": []
},
{
"id": "13",
"type": "ProteinMutation",
"text": [
"p. K237N"
],
"offsets": [
[
943,
951
]
],
"normalized": []
},
{
"id": "14",
"type": "DNAMutation",
"text": [
"T13046C"
],
"offsets": [
[
961,
968
]
],
"normalized": []
},
{
"id": "15",
"type": "ProteinMutation",
"text": [
"p.M237T"
],
"offsets": [
[
970,
977
]
],
"normalized": []
},
{
"id": "16",
"type": "DNAMutation",
"text": [
"A11470C"
],
"offsets": [
[
1124,
1131
]
],
"normalized": []
},
{
"id": "17",
"type": "DNAMutation",
"text": [
"T13046C"
],
"offsets": [
[
1133,
1140
]
],
"normalized": []
}
] | [] | [] | [] |
20 | 22104738 | [
{
"id": "24",
"type": "title",
"text": [
"Novel compound heterozygous mutation of MLYCD in a Chinese patient with malonic aciduria."
],
"offsets": [
[
0,
89
]
]
},
{
"id": "25",
"type": "abstract",
"text": [
"A 3-year-old Chinese boy presented with prominent clinical features of malonic aciduria, including developmental delay, short stature, brain abnormalities and massive excretion of malonic acid and methylmalonic acid. Molecular characterization by DNA sequencing analysis and multiplex ligation-dependent probe amplification of the MLYCD gene revealed a heterozygous mutation (c.920T>G, p.Leu307Arg) in the patient and his father and a heterozygous deletion comprising exon 1 in the patient and his mother. The missense mutation (c.920T>G) was not found in 100 healthy controls and has not been reported previously. Our findings expand the number of reported cases and add a novel entry to the repertoire of MLYCD mutations."
],
"offsets": [
[
90,
813
]
]
}
] | [
{
"id": "21",
"type": "DNAMutation",
"text": [
"c.920T>G"
],
"offsets": [
[
466,
474
]
],
"normalized": []
},
{
"id": "22",
"type": "ProteinMutation",
"text": [
"p.Leu307Arg"
],
"offsets": [
[
476,
487
]
],
"normalized": []
},
{
"id": "23",
"type": "DNAMutation",
"text": [
"c.920T>G"
],
"offsets": [
[
619,
627
]
],
"normalized": []
}
] | [] | [] | [] |
26 | 22295085 | [
{
"id": "27",
"type": "title",
"text": [
"Genetic and epigenetic alterations of the NF2 gene in sporadic vestibular schwannomas."
],
"offsets": [
[
0,
86
]
]
},
{
"id": "28",
"type": "abstract",
"text": [
"BACKGROUND: Mutations in the neurofibromatosis type 2 (NF2) tumor-suppressor gene have been identified in not only NF2-related tumors but also sporadic vestibular schwannomas (VS). This study investigated the genetic and epigenetic alterations in tumors and blood from 30 Korean patients with sporadic VS and correlated these alterations with tumor behavior. METHODOLOGY/PRINCIPAL FINDINGS: NF2 gene mutations were detected using PCR and direct DNA sequencing and three highly polymorphic microsatellite DNA markers were used to assess the loss of heterozygosity (LOH) from chromosome 22. Aberrant hypermethylation of the CpG island of the NF2 gene was also analyzed. The tumor size, the clinical growth index, and the proliferative activity assessed using the Ki-67 labeling index were evaluated. We found 18 mutations in 16 cases of 30 schwannomas (53%). The mutations included eight frameshift mutations, seven nonsense mutations, one in-frame deletion, one splicing donor site, and one missense mutation. Nine patients (30%) showed allelic loss. No patient had aberrant hypermethylation of the NF2 gene and correlation between NF2 genetic alterations and tumor behavior was not observed in this study. CONCLUSIONS/SIGNIFICANCE: The molecular genetic changes in sporadic VS identified here included mutations and allelic loss, but no aberrant hypermethylation of the NF2 gene was detected. In addition, no clear genotype/phenotype correlation was identified. Therefore, it is likely that other factors contribute to tumor formation and growth."
],
"offsets": [
[
87,
1633
]
]
}
] | [] | [] | [] | [] |
29 | 22174939 | [
{
"id": "30",
"type": "title",
"text": [
"RET mutational spectrum in Hirschsprung disease: evaluation of 601 Chinese patients."
],
"offsets": [
[
0,
84
]
]
},
{
"id": "31",
"type": "abstract",
"text": [
"Rare (RVs) and common variants of the RET gene contribute to Hirschsprung disease (HSCR; congenital aganglionosis). While RET common variants are strongly associated with the commonest manifestation of the disease (males; short-segment aganglionosis; sporadic), rare coding sequence (CDS) variants are more frequently found in the lesser common and more severe forms of the disease (females; long/total colonic aganglionosis; familial).Here we present the screening for RVs in the RET CDS and intron/exon boundaries of 601 Chinese HSCR patients, the largest number of patients ever reported. We identified 61 different heterozygous RVs (50 novel) distributed among 100 patients (16.64%). Those include 14 silent, 29 missense, 5 nonsense, 4 frame-shifts, and one in-frame amino-acid deletion in the CDS, two splice-site deletions, 4 nucleotide substitutions and a 22-bp deletion in the intron/exon boundaries and 1 single-nucleotide substitution in the 5' untranslated region. Exonic variants were mainly clustered in RET the extracellular domain. RET RVs were more frequent among patients with the most severe phenotype (24% vs. 15% in short-HSCR). Phasing RVs with the RET HSCR-associated haplotype suggests that RVs do not underlie the undisputable association of RET common variants with HSCR. None of the variants were found in 250 Chinese controls."
],
"offsets": [
[
85,
1438
]
]
}
] | [] | [] | [] | [] |
32 | 21943124 | [
{
"id": "33",
"type": "title",
"text": [
"A deletion of FGFR2 creating a chimeric IIIb/IIIc exon in a child with Apert syndrome."
],
"offsets": [
[
0,
86
]
]
},
{
"id": "34",
"type": "abstract",
"text": [
"BACKGROUND: Signalling by fibroblast growth factor receptor type 2 (FGFR2) normally involves a tissue-specific alternative splice choice between two exons (IIIb and IIIc), which generates two receptor isoforms (FGFR2b and FGFR2c respectively) with differing repertoires of FGF-binding specificity. Here we describe a unique chimeric IIIb/c exon in a patient with Apert syndrome, generated by a non-allelic homologous recombination event. CASE PRESENTATION: We present a child with Apert syndrome in whom routine genetic testing had excluded the FGFR2 missense mutations commonly associated with this disorder. The patient was found to harbour a heterozygous 1372 bp deletion between FGFR2 exons IIIb and IIIc, apparently originating from recombination between 13 bp of identical DNA sequence present in both exons. The rearrangement was not present in the unaffected parents. CONCLUSIONS: Based on the known pathogenesis of Apert syndrome, the chimeric FGFR2 protein is predicted to act in a dominant gain-of-function manner. This is likely to result from its expression in mesenchymal tissues, where retention of most of the residues essential for FGFR2b binding activity would result in autocrine activation. This report adds to the repertoire of rare cases of Apert syndrome for which a pathogenesis based on atypical FGFR2 rearrangements can be demonstrated."
],
"offsets": [
[
87,
1449
]
]
}
] | [] | [] | [] | [] |
35 | 21779184 | [
{
"id": "36",
"type": "title",
"text": [
"Detection of a-thalassemia-1 Southeast Asian and Thai type deletions and b-thalassemia 3.5-kb deletion by single-tube multiplex real-time PCR with SYBR Green1 and high-resolution melting analysis."
],
"offsets": [
[
0,
196
]
]
},
{
"id": "37",
"type": "abstract",
"text": [
"BACKGROUND: Prevention and control of thalassemia requires simple, rapid, and accurate screening tests for carrier couples who are at risk of conceiving fetuses with severe thalassemia. METHODS: Single-tube multiplex real-time PCR with SYBR Green1 and high-resolution melting (HRM) analysis were used for the identification of a-thalassemia-1 Southeast Asian (SEA) and Thai type deletions and b-thalassemia 3.5-kb gene deletion. The results were compared with those obtained using conventional gap-PCR. DNA samples were derived from 28 normal individuals, 11 individuals with a-thalassemia-1 SEA type deletion, 2 with a-thalassemia-1 Thai type deletion, and 2 with heterozygous b-thalassemia 3.5-kb gene deletion. RESULTS: HRM analysis indicated that the amplified fragments from a-thalassemia-1 SEA type deletion, a-thalassemia-1 Thai type deletion, b-thalassemia 3.5-kb gene deletion, and the wild-type b-globin gene had specific peak heights at mean melting temperature (T(m)) values of 86.89 , 85.66 , 77.24 , and 74.92 , respectively. The results obtained using single-tube multiplex real-time PCR with SYBR Green1 and HRM analysis showed 100% consistency with those obtained using conventional gap-PCR. CONCLUSIONS: Single-tube multiplex real-time PCR with SYBR Green1 and HRM analysis is a potential alternative for routine clinical screening of the common types of a- and b-thalassemia large gene deletions, since it is simple, cost-effective, and highly accurate."
],
"offsets": [
[
197,
1677
]
]
}
] | [] | [] | [] | [] |
38 | 21640722 | [
{
"id": "39",
"type": "title",
"text": [
"Xeroderma pigmentosum variant: complementary molecular approaches to detect a 13 base pair deletion in the DNA polymerase eta gene."
],
"offsets": [
[
0,
131
]
]
},
{
"id": "40",
"type": "abstract",
"text": [
"Deficiencies of DNA polymerase eta-an enzyme mediating replication past UV-induced DNA damage-predispose individuals to xeroderma pigmentosum variant (XPV) and result in a high incidence of skin cancers. We designed, developed and assessed several complementary molecular approaches to detect a genetically inherited deletion within DNA polymerase eta. RNA was reverse transcribed from XPV fibroblasts and from normal human cells, and standard polymerase chain reaction (PCR) was conducted on the cDNA targeting a region with a 13 base pair deletion within the polymerase eta gene. PCR products were subjected to restriction fragment length polymorphism (RFLP) analysis and cycle DNA sequencing. The deletion was found to eliminate a BsrGI restriction site and affected the number of resultant fragments visualized after gel electrophoresis. Cycle sequencing of polymerase eta-specific amplicons from XPV and normal cells provided a second approach for detecting the mutation. Additionally, the use of a fluorescent nucleic acid dye-EvaGreen-in real-time PCR and melt curve analysis distinguished normal and XPV patient-derived amplicons as well as heteroduplexes that represent heterozygotic carriers without the need for high resolution melt analysis-compatible software. Our approaches are easily adaptable by diagnostic laboratories that screen for or verify genetically inherited disorders and identify carriers of a defective gene."
],
"offsets": [
[
132,
1569
]
]
}
] | [] | [] | [] | [] |
41 | 21499297 | [
{
"id": "44",
"type": "title",
"text": [
"C10ORF97 is a novel tumor-suppressor gene of non-small-cell lung cancer and a functional variant of this gene increases the risk of non-small-cell lung cancer."
],
"offsets": [
[
0,
159
]
]
},
{
"id": "45",
"type": "abstract",
"text": [
"In an earlier study we showed that C10ORF97 (chromosome-10, open reading frame-97) was expressed in almost all of the tissues and cell lines tested, and that it inhibited the growth of seven tumor cell lines, including two lung carcinoma cell lines (A549 and PG). Here, we show that C10ORF97 is downregulated in non-small-cell lung cancer (NSCLC) tissue compared with normal lung tissue. Overexpression of C10ORF97 significantly suppressed human lung carcinoma A549 cell growth (proliferation and anchorage-independent growth in soft agar) and motility (migration and adhesion). This tumor-suppressive function of C10ORF97 was also verified in vivo. We further found that C10ORF97 caused G(1) arrest of A549 cells and modulated the expression level of several cell-cycle regulators (such as CDK2, cyclin-E and p27). These effects of C10ORF97 were mediated by physical association between C10ORF97 and Jun-activating domain-binding protein-1 (JAB1), and blocking of JAB1-mediated translocation of p27 from the nucleus to the cytoplasm. Together, these results indicated that C10ORF97 functions as a novel tumor suppressor by modulating several key G(1)/S-regulatory proteins by interacting with JAB1. These findings led us to hypothesize that a single-nucleotide polymorphism (SNP) in the C10ORF97 gene that affects its expression might be associated with susceptibility to NSCLC. SNP216 C>T (rs2297882) in the C10ORF97 Kozak sequence was identified, and allele T of SNP216 suppressed C10ORF97 expression in vitro and in vivo. Furthermore, the TT genotype of SNP216 was associated with an increased risk of NSCLC (adjusted odds ratio=1.73 (95% confidence interval: 1.33-2.25), P=4.6 10(-5)). These data indicated that C10ORF97 is a tumor suppressor of NSCLC progression and C10ORF97-SNP216 may serve as a predictor of NSCLC."
],
"offsets": [
[
160,
1985
]
]
}
] | [
{
"id": "42",
"type": "DNAMutation",
"text": [
"C>T"
],
"offsets": [
[
1547,
1550
]
],
"normalized": []
},
{
"id": "43",
"type": "SNP",
"text": [
"rs2297882"
],
"offsets": [
[
1552,
1561
]
],
"normalized": []
}
] | [] | [] | [] |
46 | 21695597 | [
{
"id": "53",
"type": "title",
"text": [
"MHC region and risk of systemic lupus erythematosus in African American women."
],
"offsets": [
[
0,
78
]
]
},
{
"id": "54",
"type": "abstract",
"text": [
"The major histocompatibility complex (MHC) on chromosome 6p21 is a key contributor to the genetic basis of systemic lupus erythematosus (SLE). Although SLE affects African Americans disproportionately compared to European Americans, there has been no comprehensive analysis of the MHC region in relationship to SLE in African Americans. We conducted a screening of the MHC region for 1,536 single nucleotide polymorphisms (SNPs) and the deletion of the C4A gene in a SLE case-control study (380 cases, 765 age-matched controls) nested within the prospective Black Women's Health Study. We also genotyped 1,509 ancestral informative markers throughout the genome to estimate European ancestry to control for population stratification due to population admixture. The most strongly associated SNP with SLE was the rs9271366 (odds ratio, OR = 1.70, p = 5.6 10(-5)) near the HLA-DRB1 gene. Conditional haplotype analysis revealed three other SNPs, rs204890 (OR = 1.86, p = 1.2 10(-4)), rs2071349 (OR = 1.53, p = 1.0 10(-3)), and rs2844580 (OR = 1.43, p = 1.3 10(-3)), to be associated with SLE independent of the rs9271366 SNP. In univariate analysis, the OR for the C4A deletion was 1.38, p = 0.075, but after simultaneous adjustment for the other four SNPs the odds ratio was 1.01, p = 0.98. A genotype score combining the four newly identified SNPs showed an additive risk according to the number of high-risk alleles (OR = 1.67 per high-risk allele, p < 0.0001). Our strongest signal, the rs9271366 SNP, was also associated with higher risk of SLE in a previous Chinese genome-wide association study (GWAS). In addition, two SNPs found in a GWAS of European ancestry women were confirmed in our study, indicating that African Americans share some genetic risk factors for SLE with European and Chinese subjects. In summary, we found four independent signals in the MHC region associated with risk of SLE in African American women."
],
"offsets": [
[
79,
2017
]
]
}
] | [
{
"id": "47",
"type": "SNP",
"text": [
"rs9271366"
],
"offsets": [
[
891,
900
]
],
"normalized": []
},
{
"id": "48",
"type": "SNP",
"text": [
"rs204890"
],
"offsets": [
[
1025,
1033
]
],
"normalized": []
},
{
"id": "49",
"type": "SNP",
"text": [
"rs2071349"
],
"offsets": [
[
1065,
1074
]
],
"normalized": []
},
{
"id": "50",
"type": "SNP",
"text": [
"rs2844580"
],
"offsets": [
[
1110,
1119
]
],
"normalized": []
},
{
"id": "51",
"type": "SNP",
"text": [
"rs9271366"
],
"offsets": [
[
1196,
1205
]
],
"normalized": []
},
{
"id": "52",
"type": "SNP",
"text": [
"rs9271366"
],
"offsets": [
[
1576,
1585
]
],
"normalized": []
}
] | [] | [] | [] |
55 | 21629979 | [
{
"id": "56",
"type": "title",
"text": [
"Molecular and clinical analysis of glioblastoma with an oligodendroglial component (GBMO)."
],
"offsets": [
[
0,
90
]
]
},
{
"id": "57",
"type": "abstract",
"text": [
"The genetic and clinical features of glioblastoma with an oligodendroglial component (GBMO), pathologically defined as anaplastic oligo-astrocytoma with necrosis, remain unclear. We investigated the correlation between genetic alterations and clinical outcomes in 19 GBMO patients we have encountered since 1997. Using single nucleotide polymorphism oligonucleotide genomic (SNP) microarrays, we analyzed gene amplification, loss of heterozygosity (LOH), and homozygous deletions in their whole genome. We also analyzed their overall survival (OS). Pathological studies revealed the presence of calcification in 11 and of a cyst in 9 of the 19 patients. Whole-genome analysis using SNP microarrays revealed LOH of chromosome 10 in 11, EGFR amplification in 8, 9p21 (INK4 locus) deletion in 12, PDGFR amplification in 2, and LOH of 1p19q in 2 patients. Median OS was 14 months (average 22.8 months). The pattern of genetic alterations was similar in GBMO and glioblastoma multiforme (GBM) patients, and the clinical outcomes were similar in GBMO and GBM patients."
],
"offsets": [
[
91,
1155
]
]
}
] | [] | [] | [] | [] |
58 | 22048266 | [
{
"id": "63",
"type": "title",
"text": [
"Exploratory investigation on functional significance of ETS2 and SIM2 genes in Down syndrome."
],
"offsets": [
[
0,
93
]
]
},
{
"id": "64",
"type": "abstract",
"text": [
"Trisomy of the 21{st} chromosome leads to an over dosage of several regulatory genes in Down syndrome (DS). Though allelic and genotypic combinations formed between genes are interesting, till date, this particular area has never been explored in DS. In the present investigation four SNPs in two transcription factors, Single minded 2 (SIM2) and V-ets erythroblastosis virus E26 oncogene homolog2 (ETS2), located in the 21{st} chromosome were genotyped to understand their role in DS. Genomic DNA of eastern Indian probands with DS (N=132), their parents (N=209) and ethnically matched controls (N=149) was subjected to PCR-based analyses of functionally important SNPs followed by statistical analyses. ETS2 rs461155 showed high heterozygosity in DS. Significantly lower frequency of SIM2 C-G haplotype (rs2073601-rs2073416) was noticed in individuals with DS (P value =0.01669) and their fathers (P value=0.01185). Significantly lower frequency of the A-C-C-G with higher frequency of A-C-A-G haplotypes was also noticed in subjects with DS (P value =0.02089 and 0.00588 respectively). Data obtained indicate that the rs2073601 'A' allele, responsible for nonsynonymous substitution of leucine to methionine, may have some role in DS in this population."
],
"offsets": [
[
94,
1350
]
]
}
] | [
{
"id": "59",
"type": "SNP",
"text": [
"rs461155"
],
"offsets": [
[
804,
812
]
],
"normalized": []
},
{
"id": "60",
"type": "SNP",
"text": [
"rs2073601"
],
"offsets": [
[
900,
909
]
],
"normalized": []
},
{
"id": "61",
"type": "SNP",
"text": [
"rs2073416"
],
"offsets": [
[
910,
919
]
],
"normalized": []
},
{
"id": "62",
"type": "SNP",
"text": [
"rs2073601"
],
"offsets": [
[
1215,
1224
]
],
"normalized": []
}
] | [] | [] | [] |
65 | 22028770 | [
{
"id": "77",
"type": "title",
"text": [
"APOE genotype-function relationship: evidence of -491 A/T promoter polymorphism modifying transcription control but not type 2 diabetes risk."
],
"offsets": [
[
0,
141
]
]
},
{
"id": "78",
"type": "abstract",
"text": [
"BACKGROUND: The apolipoprotein E gene (APOE) coding polymorphism modifies the risks of Alzheimer's disease, type 2 diabetes, and coronary heart disease. Aside from the coding variants, single nucleotide polymorphism (SNP) of the APOE promoter has also been shown to modify the risk of Alzheimer's disease. METHODOLOGY/PRINCIPAL FINDINGS: In this study we investigate the genotype-function relationship of APOE promoter polymorphism at molecular level and at physiological level: i.e., in transcription control of the gene and in the risk of type 2 diabetes. In molecular studies, the effect of the APOE -491A/T (rs449647) polymorphism on gene transcription was accessed by dual-luciferase reporter gene assays. The -491 A to T substitution decreased the activity (p<0.05) of the cloned APOE promoter (-1017 to +406). Using the -501 to -481 nucleotide sequence of the APOE promoter as a 'bait' to screen the human brain cDNA library by yeast one-hybrid system yielded ATF4, an endoplasmic reticulum stress response gene, as one of the interacting factors. Electrophoretic-mobility-shift assays (EMSA) and chromatin immuno-precipitation (ChIP) analyses further substantiated the physical interaction between ATF4 and the APOE promoter. Over-expression of ATF4 stimulated APOE expression whereas siRNA against ATF4 suppressed the expression of the gene. However, interaction between APOE promoter and ATF4 was not -491A/T-specific. At physiological level, the genotype-function relationship of APOE promoter polymorphism was studied in type 2 diabetes. In 630 cases and 595 controls, three APOE promoter SNPs -491A/T, -219G/T (rs405509), and +113G/C (rs440446) were genotyped and tested for association with type 2 diabetes in Hong Kong Chinese. No SNP or haplotype association with type 2 diabetes was detected. CONCLUSIONS/SIGNIFICANCE: At molecular level, polymorphism -491A/T and ATF4 elicit independent control of APOE gene expression. At physiological level, no genotype-risk association was detected between the studied APOE promoter SNPs and type 2 diabetes in Hong Kong Chinese."
],
"offsets": [
[
142,
2226
]
]
}
] | [
{
"id": "66",
"type": "DNAMutation",
"text": [
"-491 A/T"
],
"offsets": [
[
49,
57
]
],
"normalized": []
},
{
"id": "67",
"type": "DNAMutation",
"text": [
"-491A/T"
],
"offsets": [
[
745,
752
]
],
"normalized": []
},
{
"id": "68",
"type": "SNP",
"text": [
"rs449647"
],
"offsets": [
[
754,
762
]
],
"normalized": []
},
{
"id": "69",
"type": "DNAMutation",
"text": [
"-491 A to T"
],
"offsets": [
[
857,
868
]
],
"normalized": []
},
{
"id": "70",
"type": "DNAMutation",
"text": [
"-491A/T"
],
"offsets": [
[
1553,
1560
]
],
"normalized": []
},
{
"id": "71",
"type": "DNAMutation",
"text": [
"-491A/T"
],
"offsets": [
[
1748,
1755
]
],
"normalized": []
},
{
"id": "72",
"type": "DNAMutation",
"text": [
"-219G/T"
],
"offsets": [
[
1757,
1764
]
],
"normalized": []
},
{
"id": "73",
"type": "SNP",
"text": [
"rs405509"
],
"offsets": [
[
1766,
1774
]
],
"normalized": []
},
{
"id": "74",
"type": "DNAMutation",
"text": [
"+113G/C"
],
"offsets": [
[
1781,
1788
]
],
"normalized": []
},
{
"id": "75",
"type": "SNP",
"text": [
"rs440446"
],
"offsets": [
[
1790,
1798
]
],
"normalized": []
},
{
"id": "76",
"type": "DNAMutation",
"text": [
"-491A/T"
],
"offsets": [
[
2011,
2018
]
],
"normalized": []
}
] | [] | [] | [] |
79 | 21771880 | [
{
"id": "80",
"type": "title",
"text": [
"Resequencing of IRS2 reveals rare variants for obesity but not fasting glucose homeostasis in Hispanic children."
],
"offsets": [
[
0,
112
]
]
},
{
"id": "81",
"type": "abstract",
"text": [
"Our objective was to resequence insulin receptor substrate 2 (IRS2) to identify variants associated with obesity- and diabetes-related traits in Hispanic children. Exonic and intronic segments, 5' and 3' flanking regions of IRS2 ( 14.5 kb), were bidirectionally sequenced for single nucleotide polymorphism (SNP) discovery in 934 Hispanic children using 3730XL DNA Sequencers. Additionally, 15 SNPs derived from Illumina HumanOmni1-Quad BeadChips were analyzed. Measured genotype analysis tested associations between SNPs and obesity and diabetes-related traits. Bayesian quantitative trait nucleotide analysis was used to statistically infer the most likely functional polymorphisms. A total of 140 SNPs were identified with minor allele frequencies (MAF) ranging from 0.001 to 0.47. Forty-two of the 70 coding SNPs result in nonsynonymous amino acid substitutions relative to the consensus sequence; 28 SNPs were detected in the promoter, 12 in introns, 28 in the 3'-UTR, and 2 in the 5'-UTR. Two insertion/deletions (indels) were detected. Ten independent rare SNPs (MAF = 0.001-0.009) were associated with obesity-related traits (P = 0.01-0.00002). SNP 10510452_139 in the promoter region was shown to have a high posterior probability (P = 0.77-0.86) of influencing BMI, fat mass, and waist circumference in Hispanic children. SNP 10510452_139 contributed between 2 and 4% of the population variance in body weight and composition. None of the SNPs or indels were associated with diabetes-related traits or accounted for a previously identified quantitative trait locus on chromosome 13 for fasting serum glucose. Rare but not common IRS2 variants may play a role in the regulation of body weight but not an essential role in fasting glucose homeostasis in Hispanic children."
],
"offsets": [
[
113,
1895
]
]
}
] | [] | [] | [] | [] |
82 | 21790735 | [
{
"id": "83",
"type": "title",
"text": [
"A large heterozygous deletion including the entire C1 inhibitor gene in a sporadic case of hereditary angio-oedema."
],
"offsets": [
[
0,
115
]
]
},
{
"id": "84",
"type": "abstract",
"text": [
"C1 inhibitor (C1-INH) deficiency [hereditary or acquired angio-oedema (HAE or AAE)] is characterized by recurring episodes of subcutaneous or submucosal oedema. Many different mutations in the C1-INH gene have been identified as a cause of HAE. We investigated the molecular basis of the disease in a Japanese woman with sporadic HAE. Direct sequencing of genomic DNA revealed no point mutation in the C1-INH gene. Quantitative real-time PCR showed that the copy number of the C1-INH gene in the patient was half that of a healthy control. Furthermore, we identified a 650-kbp deletion on the chromosome, which included the C1-INH gene. We evaluated the correlation between the patient's attacks and her coagulation activity. The levels of D-dimer were high during the angio-oedema attacks, and often exceeded the normal range even during remission, thus the level of D-dimer reflected the activity of HAE in this patient."
],
"offsets": [
[
116,
1038
]
]
}
] | [] | [] | [] | [] |
85 | 21506149 | [
{
"id": "86",
"type": "title",
"text": [
"Phenotype of the 202 adenine deletion in the parkin gene: 40 years of follow-up."
],
"offsets": [
[
0,
80
]
]
},
{
"id": "87",
"type": "abstract",
"text": [
"BACKGROUND: We describe the four decades follow-up of 14 parkin patients belonging to two large eight-generation-long in-bred Muslim-Arab kindreds. RESULTS: All patients had a single base-pair of adenine deletion at nucleotide 202 of exon 2 (202A) of the parkin gene (all homozygous, one heterozygous). Parkinson's disease onset age was 17-68 years. Special features were intractable axial symptoms (low back pain, scoliosis, camptocormia, antecollis), postural tremor, and preserved cognition. CONCLUSIONS: The 202A deletion of the parkin gene causes early-onset Parkinson's disease with marked levodopa/STN-DBS-resistant axial features. Postural tremor and preserved cognition, even after 40 years of disease, were also evident."
],
"offsets": [
[
81,
811
]
]
}
] | [] | [] | [] | [] |
88 | 21904390 | [
{
"id": "94",
"type": "title",
"text": [
"Two novel mutations of the PAX6 gene causing different phenotype in a cohort of Chinese patients."
],
"offsets": [
[
0,
97
]
]
},
{
"id": "95",
"type": "abstract",
"text": [
"PURPOSE: Aniridia (AN) is a rare congenital panocular disorder caused by the mutations of the paired box homeotic gene 6(PAX6) gene. The PAX6gene is also involved in other anterior segment malformations including Peters anomaly. We studied the PAX6gene mutations in a cohort of affected individuals with different clinical phenotype including AN, coloboma of iris and choroid, or anterior segment malformations. PATIENTS AND METHODS: Six unrelated families and 10 sporadic patients were examined clinically. After informed consent was obtained, genomic DNA was extracted from the venous blood of all participants. Mutation screening of all exons of the PAX6gene was performed by direct sequencing of PCR-amplified DNA fragments. Multiplex ligation-dependent probe amplification (MLPA) was performed to detect large deletions. RESULTS: By clinical examination, the patients and the pedigrees were divided into the following three groups: AN, coloboma of iris and choroids, and the anterior segment malformations including peters anomaly. Sequencing of the PAX6gene, three intragenic mutations including a novel heterozygous splicing-site mutations c.357-3C>G (p.Ser119fsX) were identified in the patients of the AN group. A novel missense mutation c.643T>C (p.S216P) was detected in the anterior segment malformation group. The mutation p.S216P located in the homeodomain region of the PAX6 caused the phenotype of Peters anomaly in family A6 with different expressing. Through MLPA analysis, a large deletion including the whole PAX6gene and DKFZ p686k1684gene was detected in one sporadic patient from the AN group. Neither intragenic mutation nor large deletion was identified in the group with coloboma of iris and choroid. CONCLUSION: Our findings further confirmed that different kind of mutations might cause different ocular phenotype, and clearly clinical phenotype classification might increase the mutation detection rate of the PAX6gene."
],
"offsets": [
[
98,
2046
]
]
}
] | [
{
"id": "89",
"type": "DNAMutation",
"text": [
"c.357-3C>G"
],
"offsets": [
[
1245,
1255
]
],
"normalized": []
},
{
"id": "90",
"type": "ProteinMutation",
"text": [
"p.Ser119fsX"
],
"offsets": [
[
1257,
1268
]
],
"normalized": []
},
{
"id": "91",
"type": "DNAMutation",
"text": [
"c.643T>C"
],
"offsets": [
[
1345,
1353
]
],
"normalized": []
},
{
"id": "92",
"type": "ProteinMutation",
"text": [
"p.S216P"
],
"offsets": [
[
1355,
1362
]
],
"normalized": []
},
{
"id": "93",
"type": "ProteinMutation",
"text": [
"p.S216P"
],
"offsets": [
[
1434,
1441
]
],
"normalized": []
}
] | [] | [] | [] |
96 | 21496008 | [
{
"id": "105",
"type": "title",
"text": [
"Screening and cell-based assessment of mutations in the Aristaless-related homeobox (ARX) gene."
],
"offsets": [
[
0,
95
]
]
},
{
"id": "106",
"type": "abstract",
"text": [
"ARX mutations cause a diverse spectrum of human disorders, ranging from severe brain and genital malformations to non-syndromic intellectual disability (ID). ARX is a transcription factor with multiple domains that include four polyalanine (pA) tracts, the first two of which are frequently expanded by mutations. We progressively screened DNA samples from 613 individuals with ID initially for the most frequent ARX mutations (c.304ins(GCG)(7)'expansion' of pA1 and c.429_452dup 'dup24bp' of pA2). Five hundred samples without pA1 or pA2 mutations had the entire ARX ORF screened by single stranded polymorphism conformation (SSCP) and/or denaturing high pressure liquid chromatography (dHPLC) analysis. Overall, eight families with six mutations in ARX were identified (1.31%): five duplication mutations in pA2 (0.82%) with three new clinical reports of families with the dup24bp and two duplications larger than the dup24bp mutation discovered (dup27bp, dup33bp); and three point mutations (0.6%), including one novel mutation in the homeodomain (c.1074G>T). Four ultraconserved regions distal to ARX (uc466-469) were also screened in a subset of 94 patients, with three unique nucleotide changes identified in two (uc466, uc467). The subcellular localization of full length ARX proteins was assessed for 11 variants. Protein mislocalization increased as a function of pA2 tract length and phenotypic severity, as has been previously suggested for pA1. Similarly, protein mislocalization of the homeodomain mutations also correlated with clinical severity, suggesting an emerging genotype vs cellular phenotype correlation."
],
"offsets": [
[
96,
1723
]
]
}
] | [
{
"id": "97",
"type": "DNAMutation",
"text": [
"c.304ins(GCG)"
],
"offsets": [
[
524,
537
]
],
"normalized": []
},
{
"id": "98",
"type": "DNAMutation",
"text": [
"c.429_452dup"
],
"offsets": [
[
563,
575
]
],
"normalized": []
},
{
"id": "99",
"type": "DNAMutation",
"text": [
"dup24bp"
],
"offsets": [
[
577,
584
]
],
"normalized": []
},
{
"id": "100",
"type": "DNAMutation",
"text": [
"dup24bp"
],
"offsets": [
[
971,
978
]
],
"normalized": []
},
{
"id": "101",
"type": "DNAMutation",
"text": [
"dup24bp"
],
"offsets": [
[
1016,
1023
]
],
"normalized": []
},
{
"id": "102",
"type": "DNAMutation",
"text": [
"dup27bp"
],
"offsets": [
[
1045,
1052
]
],
"normalized": []
},
{
"id": "103",
"type": "DNAMutation",
"text": [
"dup33bp"
],
"offsets": [
[
1054,
1061
]
],
"normalized": []
},
{
"id": "104",
"type": "DNAMutation",
"text": [
"c.1074G>T"
],
"offsets": [
[
1147,
1156
]
],
"normalized": []
}
] | [] | [] | [] |
107 | 21717135 | [
{
"id": "108",
"type": "title",
"text": [
"Variation in genotype and higher virulence of a strain of Sporothrix schenckii causing disseminated cutaneous sporotrichosis."
],
"offsets": [
[
0,
125
]
]
},
{
"id": "109",
"type": "abstract",
"text": [
"Sporotrichosis is usually a localized, lymphocutaneous disease, but its disseminated type was rarely reported. The main objective of this study was to identify specific DNA sequence variation and virulence of a strain of Sporothrix schenckii isolated from the lesion of disseminated cutaneous sporotrichosis. We confirmed this strain to be S. schenckii by( ) tubulin and chitin synthase gene sequence analysis in addition to the routine mycological and partial ITS and NTS sequencing. We found a 10-bp deletion in the ribosomal NTS region of this strain, in reference to the sequence of control strains isolated from fixed cutaneous sporotrichosis. After inoculated into immunosuppressed mice, this strain caused more extensive system involvement and showed stronger virulence than the control strain isolated from a fixed cutaneous sporotrichosis. Our study thus suggests that different clinical manifestation of sporotrichosis may be associated with variation in genotype and virulence of the strain, independent of effects due to the immune status of the host."
],
"offsets": [
[
126,
1190
]
]
}
] | [] | [] | [] | [] |
110 | 21976953 | [
{
"id": "114",
"type": "title",
"text": [
"Identification of a novel FBN1 gene mutation in a Chinese family with Marfan syndrome."
],
"offsets": [
[
0,
86
]
]
},
{
"id": "115",
"type": "abstract",
"text": [
"PURPOSE: To identify the mutation in the fibrillin-1 gene (FBN1) in a Chinese family with Marfan syndrome (MFS). METHODS: Patients and family members were given complete physical, ophthalmic, and cardiovascular examinations. Genomic DNA was extracted from leukocytes of venous blood of six individuals in the family and 170 healthy Chinese individuals. All of the 65 coding exons and their flanking intronic boundaries of FBN1 were amplified in the proband by polymerase chain reaction and followed by direct sequencing. The mutation identified in the proband was screened in the other family members and the 170 healthy Chinese individuals by direct sequencing. Protein conservation analysis was performed in six species using an online ClustalW tool. Protein structure was modeled based on the Protein data bank and mutated in DeepView v4.0.1 to predict the functional consequences of the mutation. RESULTS: A novel heterozygous c.3703T>C change in exon 29 of FBN1 was detected in the proband, which resulted in the substitution of serine by proline at codon 1235 (p.S1235P). This mutation was also present in two family members but absent in the other, unaffected family members and the 170 healthy Chinese individuals. The mutant residue located in the calcium binding epidermal growth factor-like#15 domain is highly conserved among mammalian species and could probably induce conformation change of the domain. CONCLUSIONS: We indentified a novel p.S1235P mutation in FBN1, which is the causative mutation for MFS in this family. Our result expands the mutation spectrum of FBN1 and contributes to the study of the molecular pathogenesis of Marfan syndrome."
],
"offsets": [
[
87,
1750
]
]
}
] | [
{
"id": "111",
"type": "DNAMutation",
"text": [
"c.3703T>C"
],
"offsets": [
[
1018,
1027
]
],
"normalized": []
},
{
"id": "112",
"type": "ProteinMutation",
"text": [
"p.S1235P"
],
"offsets": [
[
1154,
1162
]
],
"normalized": []
},
{
"id": "113",
"type": "ProteinMutation",
"text": [
"p.S1235P"
],
"offsets": [
[
1540,
1548
]
],
"normalized": []
}
] | [] | [] | [] |
116 | 21546516 | [
{
"id": "117",
"type": "title",
"text": [
"The 57 kb deletion in cystinosis patients extends into TRPV1 causing dysregulation of transcription in peripheral blood mononuclear cells."
],
"offsets": [
[
0,
138
]
]
},
{
"id": "118",
"type": "abstract",
"text": [
"BACKGROUND: Cystinosis is an autosomal recessive disease characterised by the abnormal accumulation of lysosomal cystine. Mutations in the cystinosin gene (CTNS) represent known causes for the disease. The major cystinosis mutation is a 57 kb deletion on human chromosome 17p13 that removes the majority of CTNS and the entire adjacent gene, CARKL/SHPK. OBJECTIVES: In order to identify other genes that may influence the cystinosis pathobiological pathway, peripheral blood mononuclear cells (PBMC) were collected from cystinosis family members, and DNA and RNA extracted. RESULTS: Using whole genome transcriptional profiling, transient receptor potential vanilloid 1 (TRPV1) was found to be differentially expressed in association with cystinosis. This was verified using TaqMan qRT-PCR. There was a 72% reduction in PBMC TRPV1 mRNA levels in cystinosis individuals homozygous for the 57 kb deletion (n=6) compared to unaffected individuals without the deletion (n=6) (p=0.002). TRPV1 is a sensory receptor located on chromosome 17p13, adjacent to CARKL/SHPK. It was ascertained that the 57 kb deletion extends from exon 10 of CTNS, upstream through CARKL/SHPK, to intron 2 of TRPV1, thus deleting the first two non-coding exons. CONCLUSION: This is the first study to report that the 57 kb deletion extends into the TRPV1 gene causing dysregulation of transcription in PBMC isolated from cystinosis patients."
],
"offsets": [
[
139,
1551
]
]
}
] | [] | [] | [] | [] |
119 | 21799811 | [
{
"id": "125",
"type": "title",
"text": [
"Strong association of 677 C>T substitution in the MTHFR gene with male infertility--a study on an indian population and a meta-analysis."
],
"offsets": [
[
0,
136
]
]
},
{
"id": "126",
"type": "abstract",
"text": [
"BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme of folate and methionine metabolism, making it crucial for DNA synthesis and methylation. The objective of this study was to analyze MTHFR gene 677C>T polymorphism in infertile male individuals from North India, followed by a meta-analysis on our data and published studies. METHODOLOGY/PRINCIPAL FINDINGS: We undertook genotyping on a total of 837 individuals including well characterized infertile (N=522) and confirmed fertile (N=315) individuals. The SNP was typed by direct DNA sequencing. Chi square test was done for statistical analysis. Published studies were searched using appropriate keywords. Source of data collection for meta-analysis included 'Pubmed', 'Ovid' and 'Google Scholar'. Those studies analyzing 677C>T polymorphism in male infertility and presenting all relevant data were included in meta-analysis. The genotype data for infertile subjects and fertile controls was extracted from each study. Chi square test was done to obtain odds ratio (OR) and p-value. Meta-analysis was performed using Comprehensive Meta-analysis software (Version 2). The frequency of mutant (T) allele (p=0.0025) and genotypes (CT+TT) (p=0.0187) was significantly higher in infertile individuals in comparison to fertile controls in our case-control study. The overall summary estimate (OR) for allele and genotype meta-analysis were 1.304 (p=0.000), 1.310 (p=0.000), respectively, establishing significant association of 677C>T polymorphism with male infertility. CONCLUSIONS/SIGNIFICANCE: 677C>T substitution associated strongly with male infertility in Indian population. Allele and genotype meta-analysis also supported its strong correlation with male infertility, thus establishing it as a risk factor."
],
"offsets": [
[
137,
1925
]
]
}
] | [
{
"id": "120",
"type": "DNAMutation",
"text": [
"677 C>T"
],
"offsets": [
[
22,
29
]
],
"normalized": []
},
{
"id": "121",
"type": "DNAMutation",
"text": [
"677C>T"
],
"offsets": [
[
360,
366
]
],
"normalized": []
},
{
"id": "122",
"type": "DNAMutation",
"text": [
"677C>T"
],
"offsets": [
[
938,
944
]
],
"normalized": []
},
{
"id": "123",
"type": "DNAMutation",
"text": [
"677C>T"
],
"offsets": [
[
1639,
1645
]
],
"normalized": []
},
{
"id": "124",
"type": "DNAMutation",
"text": [
"677C>T"
],
"offsets": [
[
1708,
1714
]
],
"normalized": []
}
] | [] | [] | [] |
127 | 21976404 | [
{
"id": "128",
"type": "title",
"text": [
"Angiotensin-converting enzyme (ACE) serum levels and gene polymorphism in Egyptian patients with systemic lupus erythematosus."
],
"offsets": [
[
0,
126
]
]
},
{
"id": "129",
"type": "abstract",
"text": [
"OBJECTIVES: To investigate the association of angiotensin-converting enzyme (ACE) gene polymorphism and serum ACE level among Egyptian SLE patients and its relation to disease activity parameters. SUBJECTS AND METHODS: We enrolled 50 Egyptian female systemic lupus erythematosus (SLE) patients and 29 healthy controls. Measurement of serum ACE level was done using ELISA, and the ACE genotype was determined by polymerase chain reaction using genomic DNA from peripheral blood. RESULTS: A significant difference was found in ACE genotypes between SLE patients and controls ( (2 )= 7.84, p = 0.02). The frequency of ACE DD versus (DI and II) genotypes was significantly higher in SLE patients compared with controls ( (2 )= 5.57, p = 0.018 and OR for risk of SLE was 3.1 with 95% confidence interval: 1.198.06). Mean serum ACE level was significantly higher in the SLE group compared with controls (p = 0.006). Subjects with DD genotype had a significantly higher mean level than those with DI (p = 0.015) and II genotypes (p = 0.02). Lupus nephritis patients had a significantly higher frequency of DD versus DI and II genotypes compared with lupus patients without nephritis (Fisher's exact test, p = 0.025) and controls ( (2) =8.74, p = 0.003). SLE patients with vasculopathy had a significantly higher frequency of DD versus DI/II genotypes compared with SLE patients without vasculopathy (Fisher's exact test, p = 0.04) and controls ( (2 )= 9.84 and p = 0.002). Mean serum ACE level was significantly higher in the lupus nephritis and SLE patients with vasculopathy compared with controls (p = 0.008, p = 0.001, respectively). Significant positive correlations were found between serum ACE level and serum creatinine and 24 h proteinuria (p = 0.03, 0.009, respectively). SLE patients with DD genotype had a statistically significant higher mean SLEDAI score than those with (DI/II) genotypes (p = 0.02). Significant positive correlation was found between serum ACE levels and SLEDAI scores (p = 0.04). CONCLUSION: ACE genotype and subsequently serum ACE level could be associated with the disease activity of Egyptian SLE patients; in addition, ACE deletion polymorphism might be used as one of the predictive factors for the activity of SLE. Further studies on a larger number of patients should be done to determine the exact prevalence of ACE gene polymorphism among Egyptian SLE patients."
],
"offsets": [
[
127,
2594
]
]
}
] | [] | [] | [] | [] |
130 | 21879313 | [
{
"id": "135",
"type": "title",
"text": [
"Genotype rs8099917 near the IL28B gene and amino acid substitution at position 70 in the core region of the hepatitis C virus are determinants of serum apolipoprotein B-100 concentration in chronic hepatitis C."
],
"offsets": [
[
0,
210
]
]
},
{
"id": "136",
"type": "abstract",
"text": [
"The life cycle of the hepatitis C virus (HCV) is closely related to host lipoprotein metabolism. Serum levels of lipid are associated with the response to pegylated interferon plus ribavirin (PEG-IFN/RBV) therapy, while single nucleotide polymorphisms (SNPs) around the human interleukin 28B (IL28B) gene locus and amino acid substitutions in the core region of the HCV have been reported to affect the efficacy of PEG-IFN/RBV therapy in chronic hepatitis with HCV genotype 1b infection. The aim of this study was to elucidate the relationship between serum lipid and factors that are able to predict the efficacy of PEG-IFN/RB therapy, with specific focus on apolipoprotein B-100 (apoB-100) in 148 subjects with chronic HCV G1b infection. Our results demonstrated that both the aa 70 substitution in the core region of the HCV and the rs8099917 SNP located proximal to the IL28B were independent factors in determining serum apoB-100 and low-density lipoprotein (LDL) cholesterol levels. A significant association was noted between higher levels of apoB-100 (P = 1.1 10(-3)) and LDL cholesterol (P = 0.02) and the subjects having Arg70. A significant association was also observed between subjects carrying the rs8099917 TT responder genotype and higher levels of apoB-100 (P = 6.4 10(-3)) and LDL cholesterol (P = 4.2 10(-3)). Our results suggest that apoB-100 and LDL cholesterol are markers of impaired cellular lipoprotein pathways and/or host endogenous interferon response to HCV in chronic HCV infection. In particular, serum apoB-100 concentration might be an informative marker for judging changes in HCV-associated intracellular lipoprotein metabolism in patients carrying the rs8099917 responder genotype."
],
"offsets": [
[
211,
1934
]
]
}
] | [
{
"id": "131",
"type": "SNP",
"text": [
"rs8099917"
],
"offsets": [
[
9,
18
]
],
"normalized": []
},
{
"id": "132",
"type": "SNP",
"text": [
"rs8099917"
],
"offsets": [
[
1047,
1056
]
],
"normalized": []
},
{
"id": "133",
"type": "SNP",
"text": [
"rs8099917"
],
"offsets": [
[
1425,
1434
]
],
"normalized": []
},
{
"id": "134",
"type": "SNP",
"text": [
"rs8099917"
],
"offsets": [
[
1905,
1914
]
],
"normalized": []
}
] | [] | [] | [] |
137 | 20854438 | [
{
"id": "141",
"type": "title",
"text": [
"SLURP1 mutation-impaired T-cell activation in a family with mal de Meleda."
],
"offsets": [
[
0,
74
]
]
},
{
"id": "142",
"type": "abstract",
"text": [
"BACKGROUND: Mal de Meleda (MDM) is palmoplantar erythrokeratoderma with an autosomal recessive inheritance and is caused by a mutation in the gene encoding SLURP-1 (lymphocyte antigen 6/urokinase-type plasminogen activator receptor related protein-1). SLURP-1 is an allosteric agonist to the nicotinic acetylcholine receptor (nAchR) and it regulates epidermal homeostasis. In addition, murine studies have shown that nAchR signalling is important for the regulation of T-cell function. Among the family members, patients with the homozygous SLURP1 (previously known as ARS component B) mutation are prone to melanoma and viral infection, which might link to defective T-cell function as well as a derangement of epidermal homeostasis. OBJECTIVES: To investigate the association of the SLURP1 gene mutation with T-cell activation in a Taiwanese family with MDM. To test that SLURP-1 is essential for T-cell activation. METHODS: Human peripheral blood mononuclear cells (PBMCs) were isolated from a Taiwanese MDM family bearing the G to A substitution in nucleotide 256 in the SLURP1 gene, corresponding to a glycine to arginine substitution at amino acid 86 (G86R) in the SLURP-1 protein. PBMCs from homozygotes and wild-type controls were stimulated with anti-CD3/anti-CD28 antibodies and the level of T-cell activation was determined by the stimulation index. RESULTS: PBMCs with the heterozygous and homozygous SLURP-1 G86R mutation had defective T-cell activation. This was restored by the addition of 0 5 ug mL(-1) recombinant human SLURP-1 protein. CONCLUSIONS: Patients with MDM with the homozygous SLURP-1 G86R mutation may have an impaired T-cell activation. The presence of wild-type SLURP-1 is essential for normal T-cell activation."
],
"offsets": [
[
75,
1819
]
]
}
] | [
{
"id": "138",
"type": "ProteinMutation",
"text": [
"G86R"
],
"offsets": [
[
1233,
1237
]
],
"normalized": []
},
{
"id": "139",
"type": "ProteinMutation",
"text": [
"G86R"
],
"offsets": [
[
1496,
1500
]
],
"normalized": []
},
{
"id": "140",
"type": "ProteinMutation",
"text": [
"G86R"
],
"offsets": [
[
1689,
1693
]
],
"normalized": []
}
] | [] | [] | [] |
143 | 20728296 | [
{
"id": "144",
"type": "title",
"text": [
"Interstitial deletion of 13q14.13-q32.3 presenting with Arima syndrome and bilateral retinoblastoma."
],
"offsets": [
[
0,
100
]
]
},
{
"id": "145",
"type": "abstract",
"text": [
"A patient with a large deletion of the distal part of the long arm of chromosome 13 showed severe psychomotor retardation, a characteristic face, nystagmus, retinopathy, cystic kidney disease, and brain malformation with molar tooth sign and cerebellar vermis hypoplasia, a phenotype typical of Arima syndrome. This patient also had bilateral retinoblastoma. Fluorescent in situ hybridization and single-nucleotide-polymorphism genotyping microarray demonstrated an interstitial deletion of 54 Mbp, ranging from 13q14.13 to 13q32.3 and involving the RB1 gene. This patient is the first case of Arima syndrome, or a Joubert syndrome-related disorder, that showed linkage to chromosome 13q."
],
"offsets": [
[
101,
789
]
]
}
] | [] | [] | [] | [] |
146 | 20887110 | [
{
"id": "151",
"type": "title",
"text": [
"Impact of 5,10-methylenetetrahydrofolate reductase gene polymorphism on neural tube defects."
],
"offsets": [
[
0,
92
]
]
},
{
"id": "152",
"type": "abstract",
"text": [
"OBJECT: Neural tube defects (NTDs) are among the most common congenital malformations worldwide. Their etiology and exact mechanisms of development are incompletely understood. Many enzymes involved in folate metabolism and the genes encoding these enzymes have been studied as candidates in their etiology. A mutation in the methylenetetrahydrofolate reductase (MTHFR) gene--a C-->T transition at nucleotide 677--is one among them. The mutation results in substitution of alanine by valine at a functionally important site in the enzyme. It has been shown to be a risk factor for development of NTDs in certain populations. The present study was conducted to evaluate the role of MTHFR 677 C-->T mutation as a risk factor for NTD in the South Indian population and to determine the relative importance of the genotypes in the affected child and its mother. METHODS: Blood samples were collected from the test and the control groups. The test group consisted of children with NTDs and their mothers, while the control group consisted of apparently healthy controls. MTHFR C677T polymorphism in the 3 groups was determined by polymerase chain reaction and restriction fragment length polymorphism studies. Comparison of polymorphism in the 3 groups was using the chi-square test. RESULTS: There was a significant difference in the prevalence of MTHFR 677 C-->T mutation among the 3 groups (p = 0.002). The risk conferred by the TT genotype in the child was statistically significant (OR 12.625, 95% CI 1.430-111.465). In the mothers, however, although there was an increased prevalence of the mutation compared with the control individuals, the difference was not statistically significant (p = 0.152). CONCLUSIONS: The MTHFR 677TT genotype is considered to be a definite risk factor for development of NTDs. It is the TT genotype status of the developing embryo, rather than the TT genotype status of its mother, that is the critical genetic determinant of MTHFR-related NTD risk."
],
"offsets": [
[
93,
2073
]
]
}
] | [
{
"id": "147",
"type": "DNAMutation",
"text": [
"C-->T transition at nucleotide 677"
],
"offsets": [
[
471,
505
]
],
"normalized": []
},
{
"id": "148",
"type": "DNAMutation",
"text": [
"677 C-->T"
],
"offsets": [
[
780,
789
]
],
"normalized": []
},
{
"id": "149",
"type": "DNAMutation",
"text": [
"C677T"
],
"offsets": [
[
1165,
1170
]
],
"normalized": []
},
{
"id": "150",
"type": "DNAMutation",
"text": [
"677 C-->T"
],
"offsets": [
[
1443,
1452
]
],
"normalized": []
}
] | [] | [] | [] |
153 | 20602574 | [
{
"id": "157",
"type": "title",
"text": [
"Bikunin and a1-microglobulin/bikunin precursor (AMBP) gene mutational screening in patients with kidney stones: a case-control study."
],
"offsets": [
[
0,
133
]
]
},
{
"id": "158",
"type": "abstract",
"text": [
"OBJECTIVE: Bikunin is an inhibitor of kidney stone formation synthesized in the liver together with a(1)-microglobulin from the a(1)-microglobulin/bikunin precursor (AMBP) gene. The aim of this study was to investigate the possible association between bikunin/AMBP gene polymorphisms and urinary stone formation. MATERIAL AND METHODS: To analyse the DNA, blood samples were taken from 75 kidney stone formers who had a familial stone history, 35 sporadic stone formers and 101 healthy individuals. Four exons of bikunin gene and five parts of the promoter region of the AMBP gene were screened using single-strand conformation polymorphism and nucleotide sequence analysis. RESULTS: The Init-2 region of the promoter of AMBP gene had polymorphisms at positions -218 and -189 nt giving three different genotypes having 1,3, 2,4 and 1,2,3,4 alleles with frequencies of 17.06%, 60.19% and 22.75%, respectively, in all groups. Therefore, the Init-2 region appears to be polymorphic. As a result, the 1,3 allele has -218G and -189T complying with the reference database sequence, the 2,4 allele has -218G and T-189C substitution and the allele 1,2,3,4 genotype has substitutions at positions G-218C and T-189C. CONCLUSIONS: There were no significant differences in allele distribution between patients and controls. These common alleles exist in the Turkish population independent of stone formation. These results are the first to demonstrate the existence of bikunin and AMBP promoter polymorphism. Although the Init-2 region of the AMBP gene is the binding site for various transcription factors, the results showed no association between these observed genotypes and stone-forming phenotypes."
],
"offsets": [
[
134,
1825
]
]
}
] | [
{
"id": "154",
"type": "DNAMutation",
"text": [
"T-189C"
],
"offsets": [
[
1238,
1244
]
],
"normalized": []
},
{
"id": "155",
"type": "DNAMutation",
"text": [
"G-218C"
],
"offsets": [
[
1321,
1327
]
],
"normalized": []
},
{
"id": "156",
"type": "DNAMutation",
"text": [
"T-189C"
],
"offsets": [
[
1332,
1338
]
],
"normalized": []
}
] | [] | [] | [] |
159 | 21080147 | [
{
"id": "162",
"type": "title",
"text": [
"Novel CRELD1 gene mutations in patients with atrioventricular septal defect."
],
"offsets": [
[
0,
76
]
]
},
{
"id": "163",
"type": "abstract",
"text": [
"BACKGROUND: Atrioventricular septal defects (AVSDs) occur as clinical defects of several different syndromes, as autosomal dominant defects, and as sporadically occurring malformations. Consequently, there is genetic heterogeneity, but until recently, little is known about the genes involving in the pathogenesis of AVSD. CRELD1 gene, a novel cell adhesion molecule, is a candidate gene for AVSD. METHODS: This study included 133 patients with AVSD and 200 healthy controls. Peripheral blood samples were collected and genomic DNA was extracted from the leukocytes. CRELD1 was amplified by polymerase chain reaction (PCR) with specific primers. The sequences of PCR products were compared between the patients and controls. RESULTS: In a patient, a C-to-G transition was identified at nucleotide 857 in exon 8 that resulted in a substitution of alanine for proline at amino acid 286 in the first calcium-binding EGF domain. This patient had an isolated partial AVSD and the mutation was inherited from her mother. Another mutation was detected in a patient with a partial AVSD and evidence of Down syndrome. The heterozygous c.973G>A transition in exon 9 resulted in a substitution of lysine for glutamic acid at amino acid 325 (E325K) in the second calcium-binding EGF domain. CONCLUSIONS: Two novel CRELD1 mutations were identified in the calcium-binding EGF domain in patients with AVSD. CRELD1 is likely to be an AVSD-susceptibility gene and CRELD1 mutations may increase the risk of developing a heart defect rather than being a direct causative mutation."
],
"offsets": [
[
77,
1638
]
]
}
] | [
{
"id": "160",
"type": "DNAMutation",
"text": [
"c.973G>A"
],
"offsets": [
[
1203,
1211
]
],
"normalized": []
},
{
"id": "161",
"type": "ProteinMutation",
"text": [
"E325K"
],
"offsets": [
[
1307,
1312
]
],
"normalized": []
}
] | [] | [] | [] |
164 | 20708777 | [
{
"id": "175",
"type": "title",
"text": [
"Association of DNA polymorphisms within the CYP11B2/CYP11B1 locus and postoperative hypertension risk in the patients with aldosterone-producing adenomas."
],
"offsets": [
[
0,
154
]
]
},
{
"id": "176",
"type": "abstract",
"text": [
"OBJECTIVES: Hypertension often persists after adrenalectomy for primary aldosteronism. Traditional factors associated with postoperative hypertension were evaluated, but whether genetic determinants were involved remains poorly understood. The aim of this study was to investigate the association of DNA polymorphisms within steroid synthesis genes (CYP11B2, CYP11B1) and the postoperative resolution of hypertension in Chinese patients undergoing adrenalectomy for aldosterone-producing adenomas (APA). METHODS: Ninety-three patients with APA were assessed for postoperative resolution of hypertension. All patients were genotyped for rs1799998 (C-344 T), intron 2 conversion, rs4539 (A2718G) within CYP11B2 and rs6410 (G22 5A), rs6387 (A2803G) within CYP11B1. The associations between CYPB11B2/CYP11B1 polymorphisms and persistent postoperative hypertension were assessed by multivariate analysis. RESULTS: CYP11B2-CYP11B1 haplotype was associated with persistent postoperative hypertension in Chinese patients undergoing adrenalectomy with APA (P = .006). Specifically, the rs4539 (AA) polymorphism was associated with persistent postoperative hypertension (P = .002). Multivariate logistic regression revealed the common haplotypes H1 (AGACT), H2 (AGAWT), and H3 (AGAWC) were associated with the persistent postoperative hypertension (P = .01, 0.03, 0.005 after Bonferroni correction). Additional predictors of persistent postoperative hypertension included duration of hypertension (P <.0005), family history of hypertension (P = .001), and elevated systolic blood pressure (P = .015). CONCLUSIONS: The rs4539 (AA), H1, H2, and H3 are genetic predictors for postoperative persistence of hypertension for Chinese patients treated by adrenalectomy with APA. DNA polymorphisms at CYP11B2/B1 locus may confer susceptibility to postoperative hypertension of patients with APA."
],
"offsets": [
[
155,
2031
]
]
}
] | [
{
"id": "165",
"type": "SNP",
"text": [
"rs1799998"
],
"offsets": [
[
791,
800
]
],
"normalized": []
},
{
"id": "166",
"type": "DNAMutation",
"text": [
"C-344 T"
],
"offsets": [
[
802,
809
]
],
"normalized": []
},
{
"id": "167",
"type": "SNP",
"text": [
"rs4539"
],
"offsets": [
[
833,
839
]
],
"normalized": []
},
{
"id": "168",
"type": "DNAMutation",
"text": [
"A2718G"
],
"offsets": [
[
841,
847
]
],
"normalized": []
},
{
"id": "169",
"type": "SNP",
"text": [
"rs6410"
],
"offsets": [
[
868,
874
]
],
"normalized": []
},
{
"id": "170",
"type": "DNAMutation",
"text": [
"G22 5A"
],
"offsets": [
[
876,
882
]
],
"normalized": []
},
{
"id": "171",
"type": "SNP",
"text": [
"rs6387"
],
"offsets": [
[
885,
891
]
],
"normalized": []
},
{
"id": "172",
"type": "DNAMutation",
"text": [
"A2803G"
],
"offsets": [
[
893,
899
]
],
"normalized": []
},
{
"id": "173",
"type": "SNP",
"text": [
"rs4539"
],
"offsets": [
[
1232,
1238
]
],
"normalized": []
},
{
"id": "174",
"type": "SNP",
"text": [
"rs4539"
],
"offsets": [
[
1763,
1769
]
],
"normalized": []
}
] | [] | [] | [] |
177 | 21059483 | [
{
"id": "178",
"type": "title",
"text": [
"The GALT rush: high carrier frequency of an unusual deletion mutation of the GALT gene in the Ashkenazi population."
],
"offsets": [
[
0,
115
]
]
},
{
"id": "179",
"type": "abstract",
"text": [
"Classic galactosemia is an autosomal recessive disorder of galactose metabolism manifesting in the first weeks of life following exposure to a milk-based diet. Despite the benefit of avoidance of lactose, many patients suffer from long-term complications including neurological deficits and ovarian failure. To date, over 230 mutations have been described in the GALT gene resulting in galactosemia. Recently, an unusual mutation was characterized causing a 5.5 kb deletion, with a relatively high carrier rate in subjects of Ashkenazi Jewish (AJ) descent. The aim of this study was to estimate the carrier frequency of this mutation in the AJ population in Israel. For this purpose we developed a high-throughput methodology to genotype both normal and deleted alleles using a chip-based matrix-assisted laser desorption-time-of-flight (MALDI-TOF) mass spectrometer and Multiplex PCR. DNA samples of 760 anonymous AJ subjects were submitted for analysis, subsequently detecting six individuals heterozygous for the GALT deletion mutation, giving a carrier frequency of 1 in 127 (0.79%). Based on these results, we suggest that the method described here provides a basis for genetic screening and prenatal counseling and can potentially reduce the morbidity and mortality associated with delayed diagnosis of galactosemia in this patient population."
],
"offsets": [
[
116,
1465
]
]
}
] | [] | [] | [] | [] |
180 | 21103668 | [
{
"id": "181",
"type": "title",
"text": [
"Characterisation of two novel large F8 deletions in patients with severe haemophilia A and factor VIII inhibitors."
],
"offsets": [
[
0,
114
]
]
},
{
"id": "182",
"type": "abstract",
"text": [
"Large deletions are found in approximately 5% of patients with severe haemophilia A, but only a few deletion breakpoints have been characterised precisely so far. In this study we characterised the deletion breakpoints of two patients with severe haemophilia A, large deletions and factor VIII (FVIII) inhibitors, and subsequently established deletion-specific assays for the identification of carriers. Patient 1 had a deletion of 37,410 bp comprising exon 1 and the F8 promoter region, and a 5 bp homology (GGGCC) is present at the chromosomal fusion site. In patient 2, a deletion of 22,230 bp including parts of intron 25, exon 26 and 3'-UTR was identified. No homologous repetitive elements were found at the breakpoints. However, both breakpoints were located within long terminal repeats of endogenous retroviruses and the DNA motif TTTAAA - known to be able to bend DNA molecules - was identified at the centromeric breakpoint. By deletion-specific PCR experiments we were able to identify a heterozygous state in mother 2 (carrier) while mother 1 presented only with wild-type alleles (non-carrier). Both deletions are most likely created by DNA double strand breaks and subsequent DNA repair by the non-homologous end joining DNA repair pathway (NHEJ). The exact identification of the deletion breakpoints provides a reliable diagnostic tool for carrier identification in affected families by means of a deletion-specific PCR."
],
"offsets": [
[
115,
1551
]
]
}
] | [] | [] | [] | [] |
183 | 20682662 | [
{
"id": "184",
"type": "title",
"text": [
"Lack of association of C-C chemokine receptor 5 /\\32 deletion status with rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, and disease severity."
],
"offsets": [
[
0,
164
]
]
},
{
"id": "185",
"type": "abstract",
"text": [
"OBJECTIVE: C-C chemokine receptor 5 (CCR5) plays an important role in inflammation. A 32 base-pair (/\\32) deletion in the CCR5 gene leads to a nonfunctional receptor. This deletion has been reported to have a protective effect on the development and progression of several autoimmune diseases. We investigated whether the /\\32 deletion is associated with disease susceptibility in a population of patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and lupus nephritis (LN); and whether it is associated with disease severity. METHODS: DNA samples from 405 RA patients, 97 SLE patients, 113 LN patients, and 431 healthy controls were genotyped for the CCR5 /\\32 deletion. Differences in genotype frequencies were tested between patients and controls. Association of genotypes with disease severity was analyzed. RESULTS: Genotype frequencies of each group were in Hardy-Weinberg equilibrium. The genotype frequencies of patients did not differ significantly from controls (CCR5//\\32, /\\32//\\32: RA 18.3% and 1.2%, respectively; SLE 17.5% and 2.1%; LN 13.3% and 1.8%; controls 20.0% and 2.8%). However, there was a trend for lower /\\32 deletion allele frequency in LN patients compared to controls (p = 0.08). There was no significant association between the CCR5 status and disease severity in RA, SLE, or LN. CONCLUSION: Although an association with LN cannot be excluded, the CCR5 /\\32 deletion does not seem to be a disease susceptibility genotype for RA, SLE, or LN. No significant effect of the /\\32 deletion on disease severity was demonstrated."
],
"offsets": [
[
165,
1741
]
]
}
] | [] | [] | [] | [] |
186 | 20806042 | [
{
"id": "190",
"type": "title",
"text": [
"A novel mutation in GJA8 causing congenital cataract-microcornea syndrome in a Chinese pedigree."
],
"offsets": [
[
0,
96
]
]
},
{
"id": "191",
"type": "abstract",
"text": [
"PURPOSE: To identify the underlying genetic defect in a four-generation family of Chinese origin with autosomal dominant congenital cataract-microcornea syndrome (CCMC). METHODS: All individuals in the study underwent a full clinical examination and the details of history were collected . Genomic DNA extracted from peripheral blood was amplified by polymerase chain reaction (PCR) method and the exons of all candidate genes were sequenced. RESULTS: Direct sequencing of the encoding regions of the candidate genes revealed a heterozygous mutation c.592C-->T in exon 2 of the gap junction protein, alpha 8 (GJA8) gene. This mutation was responsible for the familial disorder through the substitution of a highly conserved arginine to tryptophan at codon 198 (p.R198W). This change co-segregated with all affected members of the family, but was not detected either in the non-carrier relatives or in the 100 normal controls. CONCLUSIONS: This report is the first to relate p.R198W mutation in GJA8 with CCMC. The result expands the mutation spectrum of GJA8 in associated with congenital cataract and microcornea, and implies that this gene has direct involvement with the development of the lens as well as the other anterior segment of the eye."
],
"offsets": [
[
97,
1344
]
]
}
] | [
{
"id": "187",
"type": "DNAMutation",
"text": [
"c.592C-->T"
],
"offsets": [
[
647,
657
]
],
"normalized": []
},
{
"id": "188",
"type": "ProteinMutation",
"text": [
"p.R198W"
],
"offsets": [
[
858,
865
]
],
"normalized": []
},
{
"id": "189",
"type": "ProteinMutation",
"text": [
"p.R198W"
],
"offsets": [
[
1071,
1078
]
],
"normalized": []
}
] | [] | [] | [] |
192 | 21159032 | [
{
"id": "193",
"type": "title",
"text": [
"Alpha2B-adrenergic receptor insertion/deletion polymorphism in women with spontaneous recurrent abortions."
],
"offsets": [
[
0,
106
]
]
},
{
"id": "194",
"type": "abstract",
"text": [
"AIM: The aim of our study was to investigate the relationship between the alpha2B-adrenoreceptor insertion/deletion (I/D) polymorphism and recurrent spontaneous abortions (RSA). METHODS: Genotyping was performed in 48 women with a history of at least three consecutive spontaneous abortions and 96 women with at least two live births and no history of pregnancy loss. Peripheral venous puncture, DNA extraction and PCR were used for the research of DD, ID and II genotype characters. RESULTS: The distribution of DD, ID and II genotypes of the alpha2B-adrenoreceptor gene was 2 (4.2%), 19 (39.6%) and 27 (56.2%) in the study group and 6 (6.5%), 28 (30.4%) and 58 (63%) in the control group, respectively. There was no significant difference between the groups. The presence of the D allele was not associated with RSA (P = 0.78, odds ratio = 0.88, 95% CI = 0.47-1.65). CONCLUSION: Our data fall short of showing any association between the presence of the alpha2B D allele and the occurrence of spontaneous abortions in the examined population."
],
"offsets": [
[
107,
1151
]
]
}
] | [] | [] | [] | [] |
195 | 20949073 | [
{
"id": "198",
"type": "title",
"text": [
"Alternative splicing at a NAGNAG acceptor site as a novel phenotype modifier."
],
"offsets": [
[
0,
77
]
]
},
{
"id": "199",
"type": "abstract",
"text": [
"Approximately 30% of alleles causing genetic disorders generate premature termination codons (PTCs), which are usually associated with severe phenotypes. However, bypassing the deleterious stop codon can lead to a mild disease outcome. Splicing at NAGNAG tandem splice sites has been reported to result in insertion or deletion (indel) of three nucleotides. We identified such a mechanism as the origin of the mild to asymptomatic phenotype observed in cystic fibrosis patients homozygous for the E831X mutation (2623G>T) in the CFTR gene. Analyses performed on nasal epithelial cell mRNA detected three distinct isoforms, a considerably more complex situation than expected for a single nucleotide substitution. Structure-function studies and in silico analyses provided the first experimental evidence of an indel of a stop codon by alternative splicing at a NAGNAG acceptor site. In addition to contributing to proteome plasticity, alternative splicing at a NAGNAG tandem site can thus remove a disease-causing UAG stop codon. This molecular study reveals a naturally occurring mechanism where the effect of either modifier genes or epigenetic factors could be suspected. This finding is of importance for genetic counseling as well as for deciding appropriate therapeutic strategies."
],
"offsets": [
[
78,
1365
]
]
}
] | [
{
"id": "196",
"type": "ProteinMutation",
"text": [
"E831X"
],
"offsets": [
[
575,
580
]
],
"normalized": []
},
{
"id": "197",
"type": "DNAMutation",
"text": [
"2623G>T"
],
"offsets": [
[
591,
598
]
],
"normalized": []
}
] | [] | [] | [] |
200 | 20651814 | [
{
"id": "201",
"type": "title",
"text": [
"Lack of association between ADRA2B-4825 gene insertion/deletion polymorphism and migraine in Chinese Han population."
],
"offsets": [
[
0,
116
]
]
},
{
"id": "202",
"type": "abstract",
"text": [
"OBJECTIVE: The present study aimed to estimate the association between susceptibility to migraine and the 12-nucleotide insertion/deletion (indel) polymorphism in promoter region of alpha(2B)-adrenergic receptor gene (ADRA2B). METHODS: A case-control study was carried out in Chinese Han population, including 368 cases of migraine and 517 controls. Genomic DNA was extracted from blood samples, and DNA fragments containing the site of polymorphism were amplified by PCR. Data were adjusted for sex, age, migraine history and family history, and analyzed using a logistic regression model. RESULTS: There was no association between indel polymorphism and migraine, at either the allele or the genotype level. CONCLUSION: These findings do not support a functional significance of ADRA2B indel polymorphism at position -4825 relative to the start codon in the far upstream region of the promoter in the present migraine subjects."
],
"offsets": [
[
117,
1046
]
]
}
] | [] | [] | [] | [] |
203 | 20534762 | [
{
"id": "209",
"type": "title",
"text": [
"Two novel mutations of the TSH-beta subunit gene underlying congenital central hypothyroidism undetectable in neonatal TSH screening."
],
"offsets": [
[
0,
133
]
]
},
{
"id": "210",
"type": "abstract",
"text": [
"CONTEXT: Patients with TSH-beta subunit defects and congenital hypothyroidism are missed by TSH-based neonatal screening. OBJECTIVE: Our objective was to report the molecular consequences of a novel splice-junction mutation and a novel missense mutation in the TSH-beta subunit gene found in two patients with congenital central hypothyroidism and conventional treatment-resistant anemia. RESULTS: Patient 1 had a homozygous G to A nucleotide change at the 5' donor splice site of exon/intron 2. This resulted in a silent change at codon 34 of the mature protein. In vitro splicing assays showed that the mutant minigene dramatically affected pre-mRNA processing, causing exon 2 to be completely skipped. The putative product from a new out-of-frame translational start point in exon 3 is expected to yield a nonsense 25-amino-acid peptide. In patient 2, sequence analysis revealed a compound heterozygosis for the already reported 313delT (C105Vfs114X) mutation and for a second novel mutation in exon 3, substituting G for A at cDNA nucleotide position 323, resulting in a C88Y change. This cysteine residue is conserved among all dimeric pituitary and placental glycoprotein hormone-beta subunits. Data from in silico analysis confirmed that the C88Y mutation would affect subunit conformation. Indeed, two different bioinformatics approaches, PolyPhen and SIFT analysis, predicted C88Y to be a damaging substitution. CONCLUSIONS: In isolated TSH deficiency, the exact molecular diagnosis is mandatory for diagnosis of isolated pituitary deficiency, delineation of prognosis, and genetic counseling. Moreover, diagnosis of central hypothyroidism should be considered in the face of severe infant anemia of uncertain etiology."
],
"offsets": [
[
134,
1862
]
]
}
] | [
{
"id": "204",
"type": "DNAMutation",
"text": [
"313delT"
],
"offsets": [
[
1066,
1073
]
],
"normalized": []
},
{
"id": "205",
"type": "ProteinMutation",
"text": [
"C105Vfs114X"
],
"offsets": [
[
1075,
1086
]
],
"normalized": []
},
{
"id": "206",
"type": "ProteinMutation",
"text": [
"C88Y"
],
"offsets": [
[
1209,
1213
]
],
"normalized": []
},
{
"id": "207",
"type": "ProteinMutation",
"text": [
"C88Y"
],
"offsets": [
[
1383,
1387
]
],
"normalized": []
},
{
"id": "208",
"type": "ProteinMutation",
"text": [
"C88Y"
],
"offsets": [
[
1519,
1523
]
],
"normalized": []
}
] | [] | [] | [] |
211 | 20529581 | [
{
"id": "214",
"type": "title",
"text": [
"A novel point mutation in CD18 causing leukocyte adhesion deficiency in a Chinese patient."
],
"offsets": [
[
0,
90
]
]
},
{
"id": "215",
"type": "abstract",
"text": [
"BACKGROUND: Leukocyte adhesion deficiency type 1 (LAD-1) is a rare, autosomal recessive inherited immunodeficiency disease characterized by recurrent severe bacterial infection, impaired pus formation, poor wound healing, associated with the mutation in the CD18 gene responsible for the ability of the leucocytes to migrate from the blood stream towards the site of inflammation. Correct and early diagnosis of LAD-1 is vital to the success of treatment and prevention of aggressive infections. The purpose of this study was to collect the clinical findings of the disease and to identify the genetic entity. METHODS: CD18 expression in the peripheral blood leukocytes from the patient, his parents and normal control was measured with flow cytometry. The entire coding regions of the CD18 gene were screened with direct sequencing genomic DNA. RESULTS: CD18 expression level on this patient's leukocyte surface was significantly decreased, with normal level in control group, his father and mother. Gene analysis revealed that this patient had a homozygous c.899A > T missense mutation in exon 8 of CD18 gene, causing the substitution of Asp to Val at the 300 amino acid. His parents were both heterozygous carriers while no such mutation was found in 50 normal controls. CONCLUSION: This study disclosed a novel point mutation Asp 300 Val located in a highly conserved region (HCR) of CD18 and confirmed the heterogeneity of the mutations causing LAD-1, indicating it was quite beneficial to establish correct and early diagnosis in children with severe LAD-1."
],
"offsets": [
[
91,
1654
]
]
}
] | [
{
"id": "212",
"type": "DNAMutation",
"text": [
"c.899A > T"
],
"offsets": [
[
1150,
1160
]
],
"normalized": []
},
{
"id": "213",
"type": "ProteinMutation",
"text": [
"Asp 300 Val"
],
"offsets": [
[
1421,
1432
]
],
"normalized": []
}
] | [] | [] | [] |
216 | 20523265 | [
{
"id": "230",
"type": "title",
"text": [
"Association study of complement factor H, C2, CFB, and C3 and age-related macular degeneration in a Han Chinese population."
],
"offsets": [
[
0,
123
]
]
},
{
"id": "231",
"type": "abstract",
"text": [
"PURPOSE: Genes in the complement pathway, including complement factor H (CFH), C2/BF, and C3, have been reported to be associated with age-related macular degeneration (AMD). Genetic variants, single-nucleotide polymorphisms (SNPs), in these genes were geno-typed for a case-control association study in a mainland Han Chinese population. METHODS: One hundred and fifty-eight patients with wet AMD, 80 patients with soft drusen, and 220 matched control subjects were recruited among Han Chinese in mainland China. Seven SNPs in CFH and two SNPs in C2, CFB', and C3 were genotyped using the ABI SNaPshot method. A deletion of 84,682 base pairs covering the CFHR1 and CFHR3 genes was detected by direct polymerase chain reaction and gel electrophoresis. RESULTS: Four SNPs, including rs3753394 (P = 0.0276), rs800292 (P = 0.0266), rs1061170 (P = 0.00514), and rs1329428 (P = 0.0089), in CFH showed a significant association with wet AMD in the cohort of this study. A haplotype containing these four SNPs (CATA) significantly increased protection of wet AMD with a P value of 0.0005 and an odds ratio of 0.29 (95% confidence interval: 0.15-0.60). Unlike in other populations, rs2274700 and rs1410996 did not show a significant association with AMD in the Chinese population of this study. None of the SNPs in CFH showed a significant association with drusen, and none of the SNPs in CFH, C2, CFB, and C3 showed a significant association with either wet AMD or drusen in the cohort of this study. The CFHR1 and CFHR3 deletion was not polymorphic in the Chinese population and was not associated with wet AMD or drusen. CONCLUSION: This study showed that SNPs rs3753394 (P = 0.0276), rs800292 (P = 0.0266), rs1061170 (P = 0.00514), and rs1329428 (P = 0.0089), but not rs7535263, rs1410996, or rs2274700, in CFH were significantly associated with wet AMD in a mainland Han Chinese population. This study showed that CFH was more likely to be AMD susceptibility gene at Chr.1q31 based on the finding that the CFHR1 and CFHR3 deletion was not polymorphic in the cohort of this study, and none of the SNPs that were significantly associated with AMD in a white population in C2, CFB, and C3 genes showed a significant association with AMD."
],
"offsets": [
[
124,
2355
]
]
}
] | [
{
"id": "217",
"type": "SNP",
"text": [
"rs3753394"
],
"offsets": [
[
906,
915
]
],
"normalized": []
},
{
"id": "218",
"type": "SNP",
"text": [
"rs800292"
],
"offsets": [
[
930,
938
]
],
"normalized": []
},
{
"id": "219",
"type": "SNP",
"text": [
"rs1061170"
],
"offsets": [
[
953,
962
]
],
"normalized": []
},
{
"id": "220",
"type": "SNP",
"text": [
"rs1329428"
],
"offsets": [
[
982,
991
]
],
"normalized": []
},
{
"id": "221",
"type": "SNP",
"text": [
"rs2274700"
],
"offsets": [
[
1298,
1307
]
],
"normalized": []
},
{
"id": "222",
"type": "SNP",
"text": [
"rs1410996"
],
"offsets": [
[
1312,
1321
]
],
"normalized": []
},
{
"id": "223",
"type": "SNP",
"text": [
"rs3753394"
],
"offsets": [
[
1780,
1789
]
],
"normalized": []
},
{
"id": "224",
"type": "SNP",
"text": [
"rs800292"
],
"offsets": [
[
1804,
1812
]
],
"normalized": []
},
{
"id": "225",
"type": "SNP",
"text": [
"rs1061170"
],
"offsets": [
[
1827,
1836
]
],
"normalized": []
},
{
"id": "226",
"type": "SNP",
"text": [
"rs1329428"
],
"offsets": [
[
1856,
1865
]
],
"normalized": []
},
{
"id": "227",
"type": "SNP",
"text": [
"rs7535263"
],
"offsets": [
[
1888,
1897
]
],
"normalized": []
},
{
"id": "228",
"type": "SNP",
"text": [
"rs1410996"
],
"offsets": [
[
1899,
1908
]
],
"normalized": []
},
{
"id": "229",
"type": "SNP",
"text": [
"rs2274700"
],
"offsets": [
[
1913,
1922
]
],
"normalized": []
}
] | [] | [] | [] |
232 | 20352162 | [
{
"id": "233",
"type": "title",
"text": [
"4G/5G polymorphism and haplotypes of SERPINE1 in atherosclerotic diseases of coronary arteries."
],
"offsets": [
[
0,
95
]
]
},
{
"id": "234",
"type": "abstract",
"text": [
"We assessed the association between common variation at the SERPINE1 (PAI1) locus and myocardial infarction (MI). Haplotype-tagging polymorphisms, including the 4G/5G deletion/insertion polymorphism and seven single nucleotide polymorphisms, were analysed in a German sample containing 3,657 cases with MI and 1,211 controls. The association between the 4G/5G polymorphism and MI was examined in a meta-analysis of data extracted from 32 studies (13,267 cases/14,716 controls). In addition, the relation between the 4G/5G polymorphism and coronary diseases, comprising MI, coronary artery disease, coronary heart disease, or the acute coronary syndrome, was assessed in a combined analysis enclosing 43 studies (17,278 cases/18,039 controls). None of the tagging polymorphisms was associated with MI in the present sample (p <or= 0.34). The adjusted odds ratio (OR) for 4G allele carriers was 1.02 (95% confidence interval [CI] 0.87-1.19) compared to the 5G5G genotype. None of 13 common (frequency >1.0%) 8-marker haplotypes was related to the risk of MI. In a meta-analysis specifically addressing the association with MI, no elevated risk was found in the carriers of the 4G allele (OR 1.07, 95% CI 0.99-1.16; p = 0.11). A more general combined analysis of coronary diseases showed a marginally increased risk in 4G allele carriers (OR 1.08, 95% CI 1.00-1.16; p = 0.044). In essence, tagging polymorphisms, including the 4G/5G polymorphism, and common haplotypes of the SERPINE1 gene region were not associated with MI in a German sample, and no compelling evidence was obtained for a relationship of the 4G/5G polymorphism to MI and coronary atherosclerosis in a meta-analysis."
],
"offsets": [
[
96,
1777
]
]
}
] | [] | [] | [] | [] |
235 | 20202300 | [
{
"id": "236",
"type": "title",
"text": [
"Recent nosocomial transmission and genotypes of multidrug-resistant Mycobacterium tuberculosis."
],
"offsets": [
[
0,
95
]
]
},
{
"id": "237",
"type": "abstract",
"text": [
"SETTING: Multidrug-resistant tuberculosis (MDR-TB) is a serious health problem in Eastern European countries, including Latvia. OBJECTIVE: To investigate the proportion of tuberculosis, including MDR-TB cases, attributable to recent transmission and risk factors associated with clustering. DESIGN: Retrospective nested case-control study. The data set incorporated a wide spectrum of social features, as well as genotypes of Mycobacterium tuberculosis isolates determined by insertion sequence 6110 restriction fragment length polymorphism analysis of PvuII cleaved genomic DNA and spoligotyping. RESULTS: In comparison with non-clustered M. tuberculosis, the Beijing genotype (OR 12.15) and multidrug resistance (OR 5.61, P < 0.01) were associated with clustering. In comparison with clustered drug-susceptible M. tuberculosis, clustering of MDR M. tuberculosis was associated with Beijing genotype (OR 41.67), previous hospitalisation (OR 18.33) and previous TB treatment (OR 17.68, P < 0.05). Direct epidemiological links in hospitals were found for almost one third (32%) of MDR Beijing cases. CONCLUSIONS: MDR cases were more likely to be found in clusters than drug-susceptible cases (74.0% vs. 33.6%). Recent nosocomial transmission of MDR-TB is an important risk factor for the spread of multiresistance, and is associated with the Beijing genotype. Special attention should be paid to infection control measures in hospitals and ambulatory treatment should be enforced."
],
"offsets": [
[
96,
1575
]
]
}
] | [] | [] | [] | [] |
238 | 20126413 | [
{
"id": "239",
"type": "title",
"text": [
"U87MG decoded: the genomic sequence of a cytogenetically aberrant human cancer cell line."
],
"offsets": [
[
0,
89
]
]
},
{
"id": "240",
"type": "abstract",
"text": [
"U87MG is a commonly studied grade IV glioma cell line that has been analyzed in at least 1,700 publications over four decades. In order to comprehensively characterize the genome of this cell line and to serve as a model of broad cancer genome sequencing, we have generated greater than 30x genomic sequence coverage using a novel 50-base mate paired strategy with a 1.4kb mean insert library. A total of 1,014,984,286 mate-end and 120,691,623 single-end two-base encoded reads were generated from five slides. All data were aligned using a custom designed tool called BFAST, allowing optimal color space read alignment and accurate identification of DNA variants. The aligned sequence reads and mate-pair information identified 35 interchromosomal translocation events, 1,315 structural variations (>100 bp), 191,743 small (<21 bp) insertions and deletions (indels), and 2,384,470 single nucleotide variations (SNVs). Among these observations, the known homozygous mutation in PTEN was robustly identified, and genes involved in cell adhesion were overrepresented in the mutated gene list. Data were compared to 219,187 heterozygous single nucleotide polymorphisms assayed by Illumina 1M Duo genotyping array to assess accuracy: 93.83% of all SNPs were reliably detected at filtering thresholds that yield greater than 99.99% sequence accuracy. Protein coding sequences were disrupted predominantly in this cancer cell line due to small indels, large deletions, and translocations. In total, 512 genes were homozygously mutated, including 154 by SNVs, 178 by small indels, 145 by large microdeletions, and 35 by interchromosomal translocations to reveal a highly mutated cell line genome. Of the small homozygously mutated variants, 8 SNVs and 99 indels were novel events not present in dbSNP. These data demonstrate that routine generation of broad cancer genome sequence is possible outside of genome centers. The sequence analysis of U87MG provides an unparalleled level of mutational resolution compared to any cell line to date."
],
"offsets": [
[
90,
2124
]
]
}
] | [] | [] | [] | [] |
241 | 20113448 | [
{
"id": "242",
"type": "title",
"text": [
"Development and validation of a SYBR Green I-based real-time polymerase chain reaction method for detection of haptoglobin gene deletion in clinical materials."
],
"offsets": [
[
0,
159
]
]
},
{
"id": "243",
"type": "abstract",
"text": [
"BACKGROUND: Anhaptoglobinemic patients run the risk of severe anaphylactic transfusion reaction because they produce serum haptoglobin (Hp) antibodies. Being homozygous for the Hp gene deletion (HP(del)) is the only known cause of congenital anhaptoglobinemia, and clinical diagnosis of HP(del) before transfusion is important to prevent anaphylactic shock. We recently developed a 5'-nuclease (TaqMan) real-time polymerase chain reaction (PCR) method. STUDY DESIGN AND METHODS: A SYBR Green I-based duplex real-time PCR assay using two forward primers and a common reverse primer followed by melting curve analysis was developed to determine HP(del) zygosity in a single tube. In addition, to obviate initial DNA extraction, we examined serially diluted blood samples as PCR templates. RESULTS: Allelic discrimination of HP(del) yielded optimal results at blood sample dilutions of 1:64 to 1:1024. The results from 2231 blood samples were fully concordant with those obtained by the TaqMan-based real-time PCR method. CONCLUSION: The detection rate of the HP(del) allele by the SYBR Green I-based method is comparable with that using the TaqMan-based method. This method is readily applicable due to its low initial cost and analyzability using economical real-time PCR machines and is suitable for high-throughput analysis as an alternative method for allelic discrimination of HP(del)."
],
"offsets": [
[
160,
1548
]
]
}
] | [] | [] | [] | [] |
244 | 20017074 | [
{
"id": "245",
"type": "title",
"text": [
"Investigation of SERPINE1 genetic polymorphism in Macedonian patients with occlusive artery disease and deep vein thrombosis."
],
"offsets": [
[
0,
125
]
]
},
{
"id": "246",
"type": "abstract",
"text": [
"BACKGROUND: Raised SERPINE1 plasma levels are related to a 1-bp guanine deletion/insertion (4G5G) polymorphism in the promoter of the SERPINE1 (plasminogen activator inhibitor 1 - PAI1) gene. Evidence suggested that the plasma levels of SERPINE1 modulate the risk of coronary artery disease; furthermore, that the 4G5G polymorphism affects the expression of the SERPINE1 gene. AIM: To analyse association of SERPINE1 polymorphism with occlusive artery disease (OAD) and deep venous thrombosis (DVT) in Macedonians in order to investigate its role as a part of candidate genes in different vascular diseases in Macedonians. METHODS: Investigated groups consisted of 82 healthy patients, 75 with OAD, and 66 with DVT. Blood samples were collected after written informed consent was obtained, and DNA was isolated from peripheral blood leukocytes. Identification of SERPINE1 polymorphism was done with CVD StripAssay (ViennaLab, Labordiagnostica GmbH, Austria). The population genetics analysis package, PyPop, was used for analysis of the SERPINE1 data. Pearson's P-values, crude odds ratio and Wald's 95% CI were calculated with Bonferroni corrected p value. RESULTS: The frequency of 4G allele for SERPINE1 was 0.538 for DVT, 0.555 for healthy participants, and 0.607 for OAD. The frequency of 5G allele for SERPINE1 was the smallest in patients with OAD (0.393) and was higher in healthy participants (0.445), and patients with DVT (0.462). Test of neutrality (Fnd) showed negative value, but was significantly different from 0 for SERPINE1 in healthy participants (p of F = 0.041) and in patients with DVT (p of F = 0.030). SERPINE1 genotypes in healthy participants and patients with OAD were not in Hardy Weinberg proportions (p = 0.019 and 0.001, respectively). No association between SERPINE1 polymorphisms and OAD or DVT was found. CONCLUSION: There is no significant relationship between SERPINE1 polymorphisms and occlusive artery disease or deep venous thrombosis in Macedonian population."
],
"offsets": [
[
126,
2125
]
]
}
] | [] | [] | [] | [] |
247 | 20005218 | [
{
"id": "257",
"type": "title",
"text": [
"A potential regulatory single nucleotide polymorphism in the promoter of the Klotho gene may be associated with essential hypertension in the Chinese Han population."
],
"offsets": [
[
0,
165
]
]
},
{
"id": "258",
"type": "abstract",
"text": [
"BACKGROUND: Mice with defects in the Klotho gene exhibit multiple aging phenotypes including arteriosclerosis. We hypothesised that the G-395A polymorphism in the promoter region of the human Klotho gene may contribute to the prevalence of Essential Hypertension (EH). METHODS: We investigate whether the G-395A polymorphism of Klotho is associated with EH in a population consisting of 215 patients with EH and 220 non-hypertensive subjects. We also tested whether a G/A substitution at the G-395A site affected the transcription level in vitro through the dual-luciferase reporter assay. RESULTS: Differences in the genotype distributions of the G-395A polymorphism between the EH and non-hypertension groups are statistically significant (P=0.032). There are differential effects of age, gender and smoking status on the association of the G-395A polymorphism with EH; the G-395A polymorphism is significantly associated with EH in subjects over 60years old, in females and in nonsmokers. A multiple logistic regression analysis indicated that the odds ratio for EH in the -395A allele carriers as compared with the control group was 0.593 (P=0.024) after adjusting for current traditional risk factors. The dual-luciferase reporter assay revealed that the -395A carrier of a 498-bp DNA fragment (containing the G-395A site) upstream of the Klotho gene has higher relative luciferase activity than the -395G carrier. CONCLUSIONS: The G-395A polymorphism of the human Klotho gene is associated with EH and may be a potential regulatory site."
],
"offsets": [
[
166,
1709
]
]
}
] | [
{
"id": "248",
"type": "DNAMutation",
"text": [
"G-395A"
],
"offsets": [
[
302,
308
]
],
"normalized": []
},
{
"id": "249",
"type": "DNAMutation",
"text": [
"G-395A"
],
"offsets": [
[
471,
477
]
],
"normalized": []
},
{
"id": "250",
"type": "DNAMutation",
"text": [
"G/A"
],
"offsets": [
[
634,
637
]
],
"normalized": []
},
{
"id": "251",
"type": "DNAMutation",
"text": [
"G-395A"
],
"offsets": [
[
658,
664
]
],
"normalized": []
},
{
"id": "252",
"type": "DNAMutation",
"text": [
"G-395A"
],
"offsets": [
[
814,
820
]
],
"normalized": []
},
{
"id": "253",
"type": "DNAMutation",
"text": [
"G-395A"
],
"offsets": [
[
1009,
1015
]
],
"normalized": []
},
{
"id": "254",
"type": "DNAMutation",
"text": [
"G-395A"
],
"offsets": [
[
1042,
1048
]
],
"normalized": []
},
{
"id": "255",
"type": "DNAMutation",
"text": [
"G-395A"
],
"offsets": [
[
1481,
1487
]
],
"normalized": []
},
{
"id": "256",
"type": "DNAMutation",
"text": [
"G-395A"
],
"offsets": [
[
1603,
1609
]
],
"normalized": []
}
] | [] | [] | [] |
259 | 19897031 | [
{
"id": "264",
"type": "title",
"text": [
"An intronic polymorphism of IRF4 gene influences gene transcription in vitro and shows a risk association with childhood acute lymphoblastic leukemia in males."
],
"offsets": [
[
0,
159
]
]
},
{
"id": "265",
"type": "abstract",
"text": [
"The interferon regulatory factor (IRF) family of DNA-binding proteins regulates expression of interferon-inducible genes with roles in the immune response and carcinogenesis. IRF4 is involved in the differentiation of B and T cells and is overexpressed in B-cell malignancies as a result of c-REL (NF-kappaB) hyperactivation. IRF4 polymorphisms are associated with susceptibility to chronic lymphoid leukemia (CLL) and non-Hodgkin lymphoma (NHL). We examined 13 IRF4 SNPs in 114 cases of childhood acute lymphoblastic leukemia (ALL) and 388 newborn controls from Wales (U.K.) using TaqMan assays. IRF4 intron 4 SNP rs12203592 showed a male-specific risk association (OR=4.4, 95% CI=1.5 to 12.6, P=0.007). Functional consequences of the C>T substitution at this SNP were assessed by cell-based reporter assays using three different cell lines. We found a repressive effect of the rs12203592 wildtype allele C on IRF4 promoter activity (P<0.001) but no repression by the variant allele in any cell line tested. Thus, homozygosity for the rs12203592 variant allele would result in increased IRF4 expression. This increase would be compounded by high levels of NF-kappaB activity in males due to the absence of estrogen. IRF4 differs from other IRFs in its anti-interferon activity which interferes with immune surveillance. We propose that a detailed study of IRF4 can provide information on the mechanism of the sex effect and the role of immune surveillance in childhood ALL development."
],
"offsets": [
[
160,
1646
]
]
}
] | [
{
"id": "260",
"type": "SNP",
"text": [
"rs12203592"
],
"offsets": [
[
775,
785
]
],
"normalized": []
},
{
"id": "261",
"type": "DNAMutation",
"text": [
"C>T"
],
"offsets": [
[
896,
899
]
],
"normalized": []
},
{
"id": "262",
"type": "SNP",
"text": [
"rs12203592"
],
"offsets": [
[
1039,
1049
]
],
"normalized": []
},
{
"id": "263",
"type": "SNP",
"text": [
"rs12203592"
],
"offsets": [
[
1196,
1206
]
],
"normalized": []
}
] | [] | [] | [] |
266 | 19766614 | [
{
"id": "270",
"type": "title",
"text": [
"A novel insertion mutation in the SEDL gene results in X-linked spondyloepiphyseal dysplasia tarda in a large Chinese pedigree."
],
"offsets": [
[
0,
127
]
]
},
{
"id": "271",
"type": "abstract",
"text": [
"BACKGROUND: Spondyloepiphyseal dysplasia tarda (SEDT) is an X-chromosome linked primary skeletal dysplasia characterized by a disproportionate short-trunked short stature, dysplasia of the large joints and flattened thoracic and lumber vertebral bodies. The objective of this study is to describe a large Chinese SEDT family with a milder phenotype and describe the molecular and clinical findings. METHODS: Eight affected males of the family were diagnosed with SEDT according to their clinical and radiological features. Direct DNA sequencing of the SEDL gene was performed. RT-PCR experiments on total RNA from blood lymphocytes were performed to confirm the defect on the SEDL gene. A short summary of all currently known SEDL gene mutations is presented. RESULTS: DNA sequencing revealed that all the affected males carried an insertion mutation (c.370-371insA) unreported previously, predicted to result in frameshifts and generate a premature stop codon (p.S124fsX127). The identical mutation was also observed in a 10-year old presymptomatic boy of the family. Eight female carriers had the typical sequencing chromatograms of heterozygotes. CONCLUSIONS: Identification of the novel insertion mutation (c.370-371insA) in this SEDT family enables carrier detection and presymptomatic/prenatal diagnosis, but also the detailed molecular and clinical features will be useful for extending the evidence for genetic and phenotypic heterogeneity in SEDT."
],
"offsets": [
[
128,
1584
]
]
}
] | [
{
"id": "267",
"type": "DNAMutation",
"text": [
"c.370-371insA"
],
"offsets": [
[
980,
993
]
],
"normalized": []
},
{
"id": "268",
"type": "ProteinMutation",
"text": [
"p.S124fsX127"
],
"offsets": [
[
1090,
1102
]
],
"normalized": []
},
{
"id": "269",
"type": "DNAMutation",
"text": [
"c.370-371insA"
],
"offsets": [
[
1339,
1352
]
],
"normalized": []
}
] | [] | [] | [] |
272 | 19730022 | [
{
"id": "273",
"type": "title",
"text": [
"Congestive heart failure with rhabdomyolysis and acute renal failure in a manifesting female carrier of Duchenne muscular dystrophy with duplication of dystrophin gene."
],
"offsets": [
[
0,
168
]
]
},
{
"id": "274",
"type": "abstract",
"text": [
"We report a 69-year-old woman who presented with dyspnea, orthopnea, and acute renal failure. She also had proximal muscle weakness suggestive of muscle disease. Her symptoms were alleviated by induced dieresis, although there was high-serum creatine kinase. Investigations for any possible etiologies of rhabdomyolysis were all negative. An X-linked recessive muscle disease was highly suspicious in view of the fact that both of her sons had suffered from muscle disease and died of respiratory failure at the ages of 22 and 29, respectively. Her muscle biopsy showed mosaic pattern with dystrophin antibody against amino-terminal, carboxy-terminal, and rod domain. Her DNA study revealed heterozygous duplication at exon 1 to 6 of the dystrophin gene as well. Therefore, she is a manifesting carrier of dystrophinopathy who was first diagnosed in late adulthood with congestive heart failure, acute episode of spontaneous rhabdomyolysis, and acute renal failure."
],
"offsets": [
[
169,
1134
]
]
}
] | [] | [] | [] | [] |
275 | 19681861 | [
{
"id": "277",
"type": "title",
"text": [
"Forty-two novel COL7A1 mutations and the role of a frequent single nucleotide polymorphism in the MMP1 promoter in modulation of disease severity in a large European dystrophic epidermolysis bullosa cohort."
],
"offsets": [
[
0,
206
]
]
},
{
"id": "278",
"type": "abstract",
"text": [
"BACKGROUND: Dystrophic epidermolysis bullosa (DEB) is a severe genetic skin blistering disorder caused by mutations in the gene COL7A1, encoding collagen VII. Recently, the MMP1 promoter single nucleotide polymorphism (SNP) rs1799750, designated as 1G 2G, was shown to be involved in modulation of disease severity in patients with recessive DEB (RDEB), and was proposed as a genetic modifier. OBJECTIVES: To identify the molecular basis of DEB in 103 individuals and to replicate the results of the MMP1 promoter SNP analysis in an independent patient group, as verification is necessary in such a rare and heterogeneous disorder. METHODS: To determine the molecular basis of the disease, we performed COL7A1 mutation screening, reverse transcription-polymerase chain reaction (PCR) and real-time quantitative PCR. The status of the MMP1 SNP was analysed by PCR and restriction enzyme digestion and verified by sequencing. RESULTS: We disclosed 42 novel COL7A1 mutations, including the first large genomic deletion of 4 kb affecting only the COL7A1 gene, and three apparently silent mutations affecting splicing. Even though the frequency of the high-risk allele was increased in patients with RDEB, no statistically significant correlation between disease severity and genotype could be made. Also, no correlation was observed with development of squamous cell carcinoma, a severe complication of DEB. CONCLUSIONS: Taken together, the results suggest that the MMP1 SNP is not the sole disease modifier in different forms of DEB, and other genetic and environmental factors contribute to the clinical phenotype."
],
"offsets": [
[
207,
1819
]
]
}
] | [
{
"id": "276",
"type": "SNP",
"text": [
"rs1799750"
],
"offsets": [
[
431,
440
]
],
"normalized": []
}
] | [] | [] | [] |
279 | 19559455 | [
{
"id": "281",
"type": "title",
"text": [
"A combination of defective DNA and protective host factors are found in a set of HIV-1 ancestral LTNPs."
],
"offsets": [
[
0,
103
]
]
},
{
"id": "282",
"type": "abstract",
"text": [
"We studied viral evolution in three HIV-1 ancestral patients from a group of LTNPs; although some minor sequences showing viral evolution were detected in all patients, the extremely low viral evolution of their viruses was shown by the phylogenetic analysis of the env sequences. Complete nucleotide sequencing of viral DNA showed the major presence of deletions. In two patients, deletions of 1088 and 228 nucleotides mapped to 5' LTR-gag region; in the other, a 247 nucleotide deletion was positioned in pol gene up to the vif ORF. These deleted genomes became dominant during follow up. Patient's viruses displayed 13 common mutations in conserved residues, from the 5' LTR to the nef gene. These mutations provided evidence of a common origin. Regarding host characteristics, one patient had HLA B2705/B5801; another B1402/B5701; whereas a third showed B3901/B4402 and was Delta32-CCR5 heterozygous. These HIV controllers presented a combination of deleted viral genomes and host protective factors."
],
"offsets": [
[
104,
1108
]
]
}
] | [
{
"id": "280",
"type": "DNAMutation",
"text": [
"Delta32"
],
"offsets": [
[
982,
989
]
],
"normalized": []
}
] | [] | [] | [] |
283 | 19542096 | [
{
"id": "284",
"type": "title",
"text": [
"Mutation of SYNE-1, encoding an essential component of the nuclear lamina, is responsible for autosomal recessive arthrogryposis."
],
"offsets": [
[
0,
129
]
]
},
{
"id": "285",
"type": "abstract",
"text": [
"Arthrogryposis multiplex congenita (AMC) is a group of disorders characterized by congenital joint contractures caused by reduced fetal movements. AMC has an incidence of 1 in 3000 newborns and is genetically heterogeneous. We describe an autosomal recessive form of myogenic AMC in a large consanguineous family. The disease is characterized by bilateral clubfoot, decreased fetal movements, delay in motor milestones, then progressive motor decline after the first decade. Genome-wide linkage analysis revealed a single locus on chromosome 6q25 with Z(max) = 3.55 at theta = 0.0 and homozygosity of the polymorphic markers at this locus in patients. Homozygous A to G nucleotide substitution of the conserved AG splice acceptor site at the junction of intron 136 and exon 137 of the SYNE-1 gene was found in patients. This mutation results in an aberrant retention of intron 136 of SYNE-1 RNA leading to premature stop codons and the lack of the C-terminal transmembrane domain KASH of nesprin-1, the SYNE-1 gene product. Mice lacking the KASH domain of nesprin-1 display a myopathic phenotype similar to that observed in patients. Altogether, these data strongly suggest that the splice site mutation of SYNE-1 gene found in the family is responsible for AMC. Recent reports have shown that mutations of the SYNE-1 gene might be responsible for autosomal recessive adult onset cerebellar ataxia. These data indicate that mutations of nesprin-1 which interacts with lamin A/C may lead to at least two distinct human disease phenotypes, myopathic or neurological, a feature similar to that found in laminopathies."
],
"offsets": [
[
130,
1744
]
]
}
] | [] | [] | [] | [] |
286 | 19477219 | [
{
"id": "287",
"type": "title",
"text": [
"Identified hidden genomic changes in mantle cell lymphoma using high-resolution single nucleotide polymorphism genomic array."
],
"offsets": [
[
0,
125
]
]
},
{
"id": "288",
"type": "abstract",
"text": [
"OBJECTIVE: Mantle cell lymphoma (MCL) is a lymphoma characterized by aberrant activation of CCND1/cyclin D1 followed by sequential genetic abnormalities. Genomic abnormalities in MCL have been extensively examined by classical cytogenetics and microarray-based comparative genomic hybridization techniques, pointing out a number of alterations in genomic regions that correlate with the neoplastic phenotype and survival. Recently, single nucleotide polymorphism genomic microarrays (SNP-chip) have been developed and used for analysis of cancer genomics. This technique allows detection of genomic changes with higher resolution, including loss of heterozygosity without changes of gene dosage, so-called acquired uniparental disomy (aUPD). MATERIALS AND METHODS: We have examined 33 samples of MCL (28 primary MCL and 5 cell lines) using the 250,000 SNP-chip from Affymetrix. RESULTS: Known alterations were confirmed by SNP arrays, including deletion of INK4A/ARF, duplication/amplification of MYC, deletion of ATM, and deletion of TP53. We also identified a duplication/amplification that occurred at 13q involving oncogenic microRNA, miR17-92. We found other genomic abnormalities, including duplication/amplification of cyclin D1, del(1p), del(6q), dup(3q) and dup(18q). Our SNP-chip analysis detected these abnormalities at high resolution, allowing us to narrow the size of the commonly deleted regions, including 1p and 6q. Our SNP-chip analysis detected a number of aUPD sites, including whole chromosome 9 aUPD and 9p aUPD. We also found an MCL case with 19p, leading to homozygous deletion of TNFSF genes. CONCLUSION: SNP-chip analysis detected in MCL very small genomic gains/losses, as well as aUPDs, which could not be detected by more conventional methods."
],
"offsets": [
[
126,
1898
]
]
}
] | [] | [] | [] | [] |
289 | 19444361 | [
{
"id": "294",
"type": "title",
"text": [
"COL3A1 2209G>A is a predictor of pelvic organ prolapse."
],
"offsets": [
[
0,
55
]
]
},
{
"id": "295",
"type": "abstract",
"text": [
"INTRODUCTION AND HYPOTHESIS: A familial tendency has been demonstrated in the etiology of pelvic organ prolapse (POP), but the specific genetic defects have not been identified. Type III collagen is an important factor in the repair of connective tissue, and gene polymorphisms may impair the tensile strength. We hypothesized that polymorphisms in the alpha I chain of the type III collagen protein-encoding gene (COL3A1) pose women at risk for POP. METHODS: In this case-control study, the prevalence of type III collagen polymorphisms was compared in women with and without signs and symptoms of POP. RESULTS: Two hundred and two POP patients and 102 normal parous controls were included. A homozygous single-nucleotide substitution in the coding region of type III collagen (COL3A1 2209G>A, rs1800255) was identified in 27 (13%) POP patients and three (3%) controls (odds ratio, 5.0; 95% confidence interval, 1.4-17.1). CONCLUSIONS: The probability of POP was higher in women with COL3A1 2209G>A. This polymorphism showed to be a relevant risk factor for POP."
],
"offsets": [
[
56,
1119
]
]
}
] | [
{
"id": "290",
"type": "DNAMutation",
"text": [
"2209G>A"
],
"offsets": [
[
7,
14
]
],
"normalized": []
},
{
"id": "291",
"type": "DNAMutation",
"text": [
"2209G>A"
],
"offsets": [
[
842,
849
]
],
"normalized": []
},
{
"id": "292",
"type": "SNP",
"text": [
"rs1800255"
],
"offsets": [
[
851,
860
]
],
"normalized": []
},
{
"id": "293",
"type": "DNAMutation",
"text": [
"2209G>A"
],
"offsets": [
[
1048,
1055
]
],
"normalized": []
}
] | [] | [] | [] |
296 | 19429807 | [
{
"id": "300",
"type": "title",
"text": [
"A novel ATP7A gross deletion mutation in a Korean patient with Menkes disease."
],
"offsets": [
[
0,
78
]
]
},
{
"id": "301",
"type": "abstract",
"text": [
"Menkes disease (MD, MIM 309400) is a fatal X-linked recessive disorder that is caused by mutations in the gene encoding ATP7A, a copper-transporting, P-type ATPase. Patients with MD are characterized by progressive hypotonia, seizures, failure to thrive, and death in early childhood. Two Korean patients were diagnosed with Menkes disease by clinical and biochemical findings. We found one missense mutation and one gross deletion in the ATP7A gene in the patients. The missense mutation in Patient 1, c.3943G>A (p.G1315R) in exon 20, was identified in a previous report. Patient 2 had a gross deletion of c.1544-?_2916+?, which was a novel mutation. The patients' mothers were shown to be carriers of the respective mutations. Prenatal DNA diagnosis in the family of Patient 2 was successfully performed, showing a male fetus with the wild-type genotype. The gross deletion is the first mutation to be identified in the ATP7A gene in Korean MD patients. We expect that our findings will be helpful in understanding the wide range of genetic variation in ATP7A in Korean MD patients."
],
"offsets": [
[
79,
1163
]
]
}
] | [
{
"id": "297",
"type": "DNAMutation",
"text": [
"c.3943G>A"
],
"offsets": [
[
582,
591
]
],
"normalized": []
},
{
"id": "298",
"type": "ProteinMutation",
"text": [
"p.G1315R"
],
"offsets": [
[
593,
601
]
],
"normalized": []
},
{
"id": "299",
"type": "DNAMutation",
"text": [
"c.1544-?_2916+?"
],
"offsets": [
[
686,
701
]
],
"normalized": []
}
] | [] | [] | [] |
302 | 19394258 | [
{
"id": "304",
"type": "title",
"text": [
"The first founder DGUOK mutation associated with hepatocerebral mitochondrial DNA depletion syndrome."
],
"offsets": [
[
0,
101
]
]
},
{
"id": "305",
"type": "abstract",
"text": [
"Deoxyguanosine kinase (dGK) deficiency is a frequent cause of mitochondrial DNA depletion associated with a hepatocerebral phenotype. In this study, we describe a new splice site mutation in the DGUOK gene and the clinical, radiologic, and genetic features of these DGUOK patients. This new DGUOK homozygous mutation (c.444-62C>A) was identified in three patients from two North-African consanguineous families with combined respiratory chain deficiencies and mitochondrial DNA depletion in the liver. Brain MRIs are normal in DGUOK patients in the literature. Interestingly, we found subtentorial abnormal myelination and moderate hyperintensity in the bilateral pallidi in our patients. This new mutation creates a cryptic splice site in intron 3 (in position -62) and is predicted to result in a larger protein with an in-frame insertion of 20 amino acids. In silico analysis of the putative impact of the insertion shows serious clashes in protein conformation: this insertion disrupts the alpha5 helix of the dGK kinase domain, rendering the protein unable to bind purine deoxyribonucleosides. In addition, a common haplotype that segregated with the disease in both families was detected by haplotype reconstruction with 10 markers (microsatellites and SNPs), which span 4.6 Mb of DNA covering the DGUOK locus. In conclusion, we report a new DGUOK splice site mutation that provide insight into a critical protein domain (dGK kinase domain) and the first founder mutation in a North-African population."
],
"offsets": [
[
102,
1610
]
]
}
] | [
{
"id": "303",
"type": "DNAMutation",
"text": [
"c.444-62C>A"
],
"offsets": [
[
420,
431
]
],
"normalized": []
}
] | [] | [] | [] |
306 | 19365571 | [
{
"id": "311",
"type": "title",
"text": [
"Macular corneal dystrophy in a Chinese family related with novel mutations of CHST6."
],
"offsets": [
[
0,
84
]
]
},
{
"id": "312",
"type": "abstract",
"text": [
"PURPOSE: To identify mutations in the carbohydrate sulfotransferase gene (CHST6) for a Chinese family with macular corneal dystrophy (MCD) and to investigate the histopathological changes in the affected cornea. METHODS: A corneal button of the proband was obtained by penetrating keratoplasty. The half button and ultrathin sections from the other half button were examined with special stains under a light microscope (LM) and an electron microscope (EM) separately. Genomic DNA was extracted from peripheral blood of 11 family members, and the coding region of CHST6 was amplified by the polymerase chain reaction (PCR) method. The PCR products were analyzed by direct sequencing and restriction enzyme digestion. RESULTS: The positive reaction to colloidal iron stain (extracellular blue accumulations in the stroma) was detected under light microscopy. Transmission electron microscopy revealed the enlargement of smooth endoplasmic reticulum and the presence of intracytoplasmic vacuoles. The compound heterozygous mutations, c.892C>T and c.1072T>C, were identified in exon 3 of CHST6 in three patients. The two transversions resulted in the substitution of a stop codon for glutamine at codon 298 (p.Q298X) and a missense mutation at codon 358, tyrosine to histidine (p.Y358H). The six unaffected family individuals carried alternative heterozygous mutations. These two mutations were not detected in any of the 100 control subjects. CONCLUSIONS: Those novel compound heterozygous mutations were thought to contribute to the loss of CHST6 function, which induced the abnormal metabolism of keratan sulfate (KS) that deposited in the corneal stroma. It could be proved by the observation of a positive stain reaction and the enlarged collagen fibers as well as hyperplastic fibroblasts under microscopes."
],
"offsets": [
[
85,
1895
]
]
}
] | [
{
"id": "307",
"type": "DNAMutation",
"text": [
"c.892C>T"
],
"offsets": [
[
1117,
1125
]
],
"normalized": []
},
{
"id": "308",
"type": "DNAMutation",
"text": [
"c.1072T>C"
],
"offsets": [
[
1130,
1139
]
],
"normalized": []
},
{
"id": "309",
"type": "ProteinMutation",
"text": [
"p.Q298X"
],
"offsets": [
[
1290,
1297
]
],
"normalized": []
},
{
"id": "310",
"type": "ProteinMutation",
"text": [
"p.Y358H"
],
"offsets": [
[
1360,
1367
]
],
"normalized": []
}
] | [] | [] | [] |
313 | 19298002 | [
{
"id": "316",
"type": "title",
"text": [
"Genetic polymorphism in chemokine CCL22 and susceptibility to Helicobacter pylori infection-related gastric carcinoma."
],
"offsets": [
[
0,
118
]
]
},
{
"id": "317",
"type": "abstract",
"text": [
"BACKGROUND: Gastric carcinoma is widely considered to be related to Helicobacter pylori infection, and the chemokine (C-C motif) ligand 22 (CCL22) plays an important role in suppressing immune responses against H. pylori and tumor cells. In this study, the authors examined the association between single nucleotide polymorphisms (SNPs) in the CCL22 gene and the risk of gastric carcinoma. METHODS: Information on SNPs in the CCL22 coding region was obtained from the HapMap Project database. Genotypes were determined in a case-control cohort that consisted of 1001 patients with gastric carcinoma and 1066 controls, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were computed by using a logistic regression model. Serum H. pylori antibody levels were measured by using an enzyme-linked immunosorbent assay. RESULTS: The 16C-->A SNP (reference SNP no. 4359426) in exon 1 of the CCL22 gene, which causes a 2 aspartate (2Asp) to 2 alanine (2Ala) substitution in the CCL22 protein, was associated with a significantly increased risk of gastric carcinoma. Individuals who were homozygous for the Ala/Ala genotype had an OR of 2.27 (95% CI, 1.28-4.02) compared with individuals who had the Asp/Asp genotype. Stratification analysis indicated that the association was more pronounced among men (OR, 2.64; 95% CI, 1.29-5.41) and among younger individuals (OR, 2.85; 95% CI, 1.36-5.96) compared with women and older individuals. Moreover, a multiplicative joint effect between the CCL22 SNP and H. pylori infection that intensified the risk was observed (OR for the presence of both Ala/Ala genotype and H. pylori infection, 18.37; 95% CI, 2.30-146.67). CONCLUSIONS: The results from this study suggested that the CCL22 polymorphism is associated with an increase risk of developing H. pylori infection-related gastric carcinoma."
],
"offsets": [
[
119,
1956
]
]
}
] | [
{
"id": "314",
"type": "DNAMutation",
"text": [
"16C-->A"
],
"offsets": [
[
956,
963
]
],
"normalized": []
},
{
"id": "315",
"type": "SNP",
"text": [
"reference SNP no. 4359426"
],
"offsets": [
[
969,
994
]
],
"normalized": []
}
] | [] | [] | [] |
318 | 19132389 | [
{
"id": "319",
"type": "title",
"text": [
"Impact of pepsinogen C polymorphism on individual susceptibility to gastric cancer and its precancerous conditions in a Northeast Chinese population."
],
"offsets": [
[
0,
149
]
]
},
{
"id": "320",
"type": "abstract",
"text": [
"PURPOSE: Human pepsinogen C (PGC) is an aspartic protease produced specifically by the gastric mucosa, and is considered as a mature marker of gastric epithelium. This study examined the contributions of PGC polymorphisms and the Helicobacter pylori (H. pylori) infection to the risk of gastric cancer (GC), and its precancerous conditions in a Northeast Chinese population. METHODS: The PGC insertion/deletion polymorphism was evaluated by polymerase chain reaction analysis, followed by direct DNA sequencing in 564 cases of GC, atrophic gastritis (AG), gastric ulcer (GU) and superficial gastritis (as control). All cases were frequency-matched 1:1 by gender and age (+/-5). H. pylori infection was identified by serum anti-H. pylori IgG measurement through enzyme-linked immunosorbent assay. RESULTS: Patients with a homozygous PGC allele 1 genotype had a significant risk of AG [adjusted odds ratio (OR) 3.11; 95% confidence interval (CI) 1.44-6.71] or of GC (OR 3.00; 95% CI 1.38-6.51), and a significantly elevated risk of intestinal metaplasia (OR 1.90, 95% CI 1.11-3.27). PGC polymorphism with H. pylori infection increased risk of GU (OR 8.69; 95% CI 1.01-74.69), and AG (OR 11.12; 95% CI 1.37-90.84) or GC (OR 10.61; 95% CI 1.28-87.79) in a super-multiplicative manner. The S value was 5.40, 6.48 and 4.34; and the AP value was 72.09, 7.00 and 69.69%, respectively. CONCLUSIONS: The PGC gene polymorphism increases an individual's susceptibility to GC and its precancerous conditions. Moreover, the PGC gene polymorphism shows a positive link to H. pylori infection in the development of GC."
],
"offsets": [
[
150,
1752
]
]
}
] | [] | [] | [] | [] |
321 | 19129715 | [
{
"id": "325",
"type": "title",
"text": [
"Three novel IGFALS gene mutations resulting in total ALS and severe circulating IGF-I/IGFBP-3 deficiency in children of different ethnic origins."
],
"offsets": [
[
0,
145
]
]
},
{
"id": "326",
"type": "abstract",
"text": [
"BACKGROUND/AIMS: To date, four mutations in the IGFALS gene have been reported. We now describe two children of different ethnic background with total acid-labile subunit (ALS) and severe circulating IGF-I/IGFBP-3 deficiencies resulting from three novel mutations in the IGFALS gene. PATIENTS/METHODS: Serum and DNA of patients were analyzed. RESULTS: Case 1 is a 12-year-old boy of Mayan origin. Case 2 is a 5-year-old girl of Jewish/Eastern European (Polish, Russian, Austrian-Hungarian)/Icelandic/European (French, English) ancestry. The reported cases had moderate short stature (-2.91 and -2.14 SDS, respectively), nondetectable serum ALS and extremely low serum concentrations of IGF-I and IGFBP-3. Case 1 harbored a novel homozygous 1308_1316 dup9 mutation in a highly conserved leucine-rich repeat (LRR) 17 motif of exon 2, representing an in-frame insertion of 3 amino acids, LEL. Case 2 harbored a novel heterozygous C60S/L244F mutation in exon 2, located within a highly conserved LRR 1 and LRR 9, respectively. CONCLUSIONS: The identification of additional novel IGFALS mutations, resulting in severe IGF-I/IGFBP-3 and ALS deficiencies, supports IGFALS as a candidate gene of the GH/IGF system, implicated in the pathogenesis of primary IGF deficiency, and represents an important part of its differential diagnosis."
],
"offsets": [
[
146,
1474
]
]
}
] | [
{
"id": "322",
"type": "DNAMutation",
"text": [
"1308_1316 dup9"
],
"offsets": [
[
886,
900
]
],
"normalized": []
},
{
"id": "323",
"type": "ProteinMutation",
"text": [
"C60S"
],
"offsets": [
[
1073,
1077
]
],
"normalized": []
},
{
"id": "324",
"type": "ProteinMutation",
"text": [
"L244F"
],
"offsets": [
[
1078,
1083
]
],
"normalized": []
}
] | [] | [] | [] |
327 | 19110214 | [
{
"id": "330",
"type": "title",
"text": [
"A recessive skeletal dysplasia, SEMD aggrecan type, results from a missense mutation affecting the C-type lectin domain of aggrecan."
],
"offsets": [
[
0,
132
]
]
},
{
"id": "331",
"type": "abstract",
"text": [
"Analysis of a nuclear family with three affected offspring identified an autosomal-recessive form of spondyloepimetaphyseal dysplasia characterized by severe short stature and a unique constellation of radiographic findings. Homozygosity for a haplotype that was identical by descent between two of the affected individuals identified a locus for the disease gene within a 17.4 Mb interval on chromosome 15, a region containing 296 genes. These genes were assessed and ranked by cartilage selectivity with whole-genome microarray data, revealing only two genes, encoding aggrecan and chondroitin sulfate proteoglycan 4, that were selectively expressed in cartilage. Sequence analysis of aggrecan complementary DNA from an affected individual revealed homozygosity for a missense mutation (c.6799G --> A) that predicts a p.D2267N amino acid substitution in the C-type lectin domain within the G3 domain of aggrecan. The D2267 residue is predicted to coordinate binding of a calcium ion, which influences the conformational binding loops of the C-type lectin domain that mediate interactions with tenascins and other extracellular-matrix proteins. Expression of the normal and mutant G3 domains in mammalian cells showed that the mutation created a functional N-glycosylation site but did not adversely affect protein trafficking and secretion. Surface-plasmon-resonance studies showed that the mutation influenced the binding and kinetics of the interactions between the aggrecan G3 domain and tenascin-C. These findings identify an autosomal-recessive skeletal dysplasia and a significant role for the aggrecan C-type lectin domain in regulating endochondral ossification and, thereby, height."
],
"offsets": [
[
133,
1826
]
]
}
] | [
{
"id": "328",
"type": "DNAMutation",
"text": [
"c.6799G --> A"
],
"offsets": [
[
922,
935
]
],
"normalized": []
},
{
"id": "329",
"type": "ProteinMutation",
"text": [
"p.D2267N"
],
"offsets": [
[
953,
961
]
],
"normalized": []
}
] | [] | [] | [] |
332 | 19101703 | [
{
"id": "333",
"type": "title",
"text": [
"Study of a Taiwanese family with oculopharyngeal muscular dystrophy."
],
"offsets": [
[
0,
68
]
]
},
{
"id": "334",
"type": "abstract",
"text": [
"BACKGROUND: Oculopharyngeal muscular dystrophy (OPMD) is a late onset autosomal dominant muscle disorder. OPMD is caused by a short trinucleotide repeat expansion encoding an expanded polyalanine tract in the polyadenylate binding-protein nuclear 1 (PABPN1) gene. We identified and characterized a PABPN1 mutation in a Taiwanese family with OPMD. METHODS: The phenotypic and genotypic characteristics of all subjects were evaluated in a Taiwanese OPMD family. Genetic alterations in the PABPN1 gene were identified using PCR and DNA sequencing. RESULTS: Ten subjects with OPMD (6 symptomatic and 4 asymptomatic) within the Taiwanese family carried a novel mutation in the PABPN1 gene. The normal (GCG)6(GCA)3GCG sequence was replaced by (GCG)6(GCA)(GCG)4(GCA)3GCG due to an insertion of (GCG)4GCA into the normal allele in the Taiwanese OPMD subjects. CONCLUSIONS: In contrast to a single GCG expansion in most of OPMD patients in the literature, an insertion of (GCG)4GCA in the PABPN1 gene was found in the Taiwanese OPMD subjects. The identification of this mutation appears to support the molecular mechanism of unequal cross-over of two PABPN1 alleles."
],
"offsets": [
[
69,
1226
]
]
}
] | [] | [] | [] | [] |
335 | 19082493 | [
{
"id": "340",
"type": "title",
"text": [
"Combination of polymorphisms within 5' and 3' untranslated regions of thymidylate synthase gene modulates survival in 5 fluorouracil-treated colorectal cancer patients."
],
"offsets": [
[
0,
168
]
]
},
{
"id": "341",
"type": "abstract",
"text": [
"In the present study we explored the effect of three polymorphisms of the TS gene on overall and progression- free survival of colorectal cancer (CRC) patients subjected to 5FU chemotherapy. A 28 bp variable number of tandem repeats (VNTR), a G/C single nucleotide polymorphism (SNP), and a deletion of 6 bp at position 1494 were studied. The possible combined effect of these DNA polymorphisms on the clinical outcome of patients was also evaluated. A retrospective study was carried out on paraffin-embedded sections from 113 patients diagnosed of advanced CRC. TS genotyping methods were polymerase chain reaction (PCR) for VNTR and PCR, followed by restriction length fragment polymorphism (PCR-RFLP) for SNP and ins/del 6 bp. To study the combined effect of TS polymorphisms, four categories were defined accordingly to the level of expression attributed to SNP and ins/del 6 bp genotypes: C_allele 6-, C_6+/6+, G_allele6- and G_6+/6+. VNTR and ins/del 6 bp genotypes varied with tumour anatomical site: 2R/2R genotype was rare in left-sided tumours (7.0% vs. 26.3% of right-sided and 24.1% of rectal cancers; P<0.01), where the variant allele 6- was very frequent (69.0%). Instead, most patients with right-sided tumours were wild-type homozygous 6+/6+ (63.9%) (P<0.01). Heterozygous 6+/6- genotype was more frequent among tumours classified as C (50.0%) and D (76.5%) Dukes stages (P=0.05). None of the studied polymorphisms alone affected overall or progression-free survival (PFS). C_6+/6+ and G_6+/6+ combined genotypes were respectively associated to the best and worst PFS (P=0.03 when compared with each other), while combinations carrying the allele 6- determined an intermediate evolution that might be indicative of a variable response to chemotherapy. The rate of Dukes B stage tumours was unexpectedly high (59.1%) among patients with the unfavourable G_6+/6+ combination. In our study the combination of high TS expression genotypes G_6+/6+ identifies a group of high risk within CRC patients treated with 5FU."
],
"offsets": [
[
169,
2198
]
]
}
] | [
{
"id": "336",
"type": "DNAMutation",
"text": [
"G/C"
],
"offsets": [
[
412,
415
]
],
"normalized": []
},
{
"id": "337",
"type": "DNAMutation",
"text": [
"ins/del 6 bp"
],
"offsets": [
[
886,
898
]
],
"normalized": []
},
{
"id": "338",
"type": "DNAMutation",
"text": [
"ins/del 6 bp"
],
"offsets": [
[
1040,
1052
]
],
"normalized": []
},
{
"id": "339",
"type": "DNAMutation",
"text": [
"ins/del 6 bp"
],
"offsets": [
[
1119,
1131
]
],
"normalized": []
}
] | [] | [] | [] |
342 | 19047089 | [
{
"id": "343",
"type": "title",
"text": [
"Genome-wide loss of heterozygosity and uniparental disomy in BRCA1/2-associated ovarian carcinomas."
],
"offsets": [
[
0,
99
]
]
},
{
"id": "344",
"type": "abstract",
"text": [
"PURPOSE: The importance of the BRCA gene products in maintaining genomic stability led us to hypothesize that BRCA-associated and sporadic ovarian cancers would have distinctive genetic profiles despite similarities in histologic appearance. EXPERIMENTAL DESIGN: A whole-genome copy number analysis of fresh, frozen, papillary serous ovarian cancer DNA was done using the Affymetrix 50K Xba Mapping Array using each patient's normal genomic DNA as the matched control. Loss of heterozygosity and copy number abnormalities were summarized to define regions of amplification, deletion, or uniparental disomy (UPD), defined as loss of one allele and duplication of the remaining allele. Genomic abnormalities were compared between BRCA-associated and sporadic tumors. RESULTS: We compared 6 BRCA-associated with 14 sporadic papillary serous ovarian carcinomas. Genetic instability, measured by percentage of genome altered, was more pronounced in BRCA-associated tumors (median, 86.6%; range, 54-100%) than sporadic tumors (median, 43.6%; range, 2-83%; P = 0.009). We used frequency plots to show the proportion of cases affected by each type abnormality at each genomic region. BRCA-associated tumors showed genome-wide loss of heterozygosity primarily due to the occurrence of UPD rather than deletion. UPD was found in 100% of the BRCA-associated and 50% of the sporadic tumors profiled. CONCLUSIONS: This study reports on a previously underappreciated genetic phenomenon of UPD, which occurs frequently in ovarian cancer DNA. We observed distinct genetic patterns between BRCA-associated and sporadic ovarian cancers, suggesting that these papillary serous tumors arise from different molecular pathways."
],
"offsets": [
[
100,
1805
]
]
}
] | [] | [] | [] | [] |
345 | 19037252 | [
{
"id": "346",
"type": "title",
"text": [
"Mutations in phospholipase C epsilon 1 are not sufficient to cause diffuse mesangial sclerosis."
],
"offsets": [
[
0,
95
]
]
},
{
"id": "347",
"type": "abstract",
"text": [
"Diffuse mesangial sclerosis occurs as an isolated abnormality or as a part of a syndrome. Recently, mutations in phospholipase C epsilon 1 (PLCE1) were found to cause a nonsyndromic, autosomal recessive form of this disease. Here we describe three children from one consanguineous kindred of Pakistani origin with diffuse mesangial sclerosis who presented with congenital or infantile nephrotic syndrome. Homozygous mutations in PLCE1 (also known as KIAA1516, PLCE, or NPHS3) were identified following genome-wide mapping of single-nucleotide polymorphisms. All affected children were homozygous for a four-basepair deletion in exon 3, which created a premature translational stop codon. Analysis of the asymptomatic father of two of the children revealed that he was also homozygous for the same mutation. We conclude this nonpenetrance may be due to compensatory mutations at a second locus and that mutation within PLCE1 is not always sufficient to cause diffuse mesangial sclerosis."
],
"offsets": [
[
96,
1082
]
]
}
] | [] | [] | [] | [] |
348 | 19012332 | [
{
"id": "350",
"type": "title",
"text": [
"Somatic TP53 mutation mosaicism in a patient with Li-Fraumeni syndrome."
],
"offsets": [
[
0,
71
]
]
},
{
"id": "351",
"type": "abstract",
"text": [
"We present a girl who developed adrenocortical adenoma at the age of 1 year and osteosarcoma at the age of 5 years. There was no history of cancer in her parents and their relatives. However, both tumors were typical for the Li-Fraumeni syndrome (LFS), and the patient met criteria for germline TP53 mutation testing. A mutation in codon 282 (Arg282Trp) was identified in her blood lymphocyte genomic DNA. The substitution was found in neither of her parents, which indicated a possibility of a de novo mutation. Unexpectedly, sequencing of the DNA of the patient repeatedly showed allelic imbalance in favor of the normal allele. This observation prompted us to investigate the putative somatic mosaicism in the patient consisting of normal cells and cells heterozygous for the mutation. The imbalance was also examined in two other non-invasively sampled tissues, buccal cells, and cells from the urine sediment, and sequencing was confirmed with two other independent methods. While the findings in blood and the urine sediment were similar, in buccal cells both alleles were present in equal amounts. The allele ratio in lymphocytes was consistent with a mosaic where about 2/3 of cells carried two normal alleles and only 1/3 was heterozygous for the mutation. Despite the mosaicism the girl developed two early childhood tumors of mesodermal origin, and her phenotype was thus not milder than that of other germline TP53 mutation carriers. To our knowledge this is the first description of somatic mosaicism for a de novo TP53 mutation in LFS."
],
"offsets": [
[
72,
1621
]
]
}
] | [
{
"id": "349",
"type": "ProteinMutation",
"text": [
"Arg282Trp"
],
"offsets": [
[
415,
424
]
],
"normalized": []
}
] | [] | [] | [] |
352 | 18838613 | [
{
"id": "353",
"type": "title",
"text": [
"A comprehensive analysis of the CDKN2A gene in childhood acute lymphoblastic leukemia reveals genomic deletion, copy number neutral loss of heterozygosity, and association with specific cytogenetic subgroups."
],
"offsets": [
[
0,
208
]
]
},
{
"id": "354",
"type": "abstract",
"text": [
"Inactivation of the tumor suppressor gene, CDKN2A, can occur by deletion, methylation, or mutation. We assessed the principal mode of inactivation in childhood acute lymphoblastic leukemia (ALL) and frequency in biologically relevant subgroups. Mutation or methylation was rare, whereas genomic deletion occurred in 21% of B-cell precursor ALL and 50% of T-ALL patients. Single nucleotide polymorphism arrays revealed copy number neutral (CNN) loss of heterozygosity (LOH) in 8% of patients. Array-based comparative genomic hybridization demonstrated that the mean size of deletions was 14.8 Mb and biallelic deletions composed a large and small deletion (mean sizes, 23.3 Mb and 1.4 Mb). Among 86 patients, only 2 small deletions were below the resolution of detection by fluorescence in situ hybridization. Patients with high hyperdiploidy, ETV6-RUNX1, or 11q23/MLL rearrangements had low rates of deletion (11%, 15%, 13%), whereas patients with t(9;22), t(1;19), TLX3, or TLX1 rearrangements had higher frequencies (61%, 42%, 78%, and 89%). In conclusion, CDKN2A deletion is a significant secondary abnormality in childhood ALL strongly correlated with phenotype and genotype. The variation in the incidence of CDKN2A deletions by cytogenetic subgroup may explain its inconsistent association with outcome. CNN LOH without apparent CDKN2A inactivation suggests the presence of other relevant genes in this region."
],
"offsets": [
[
209,
1625
]
]
}
] | [] | [] | [] | [] |
355 | 18827003 | [
{
"id": "362",
"type": "title",
"text": [
"A novel point mutation in the amino terminal domain of the human glucocorticoid receptor (hGR) gene enhancing hGR-mediated gene expression."
],
"offsets": [
[
0,
139
]
]
},
{
"id": "363",
"type": "abstract",
"text": [
"CONTEXT: Interindividual variations in glucocorticoid sensitivity have been associated with manifestations of cortisol excess or deficiency and may be partly explained by polymorphisms in the human glucocorticoid receptor (hGR) gene. We studied a 43-yr-old female, who presented with manifestations consistent with tissue-selective glucocorticoid hypersensitivity. We detected a novel, single, heterozygous nucleotide (G --> C) substitution at position 1201 (exon 2) of the hGR gene, which resulted in aspartic acid to histidine substitution at amino acid position 401 in the amino-terminal domain of the hGRalpha. We investigated the molecular mechanisms of action of the natural mutant receptor hGRalphaD401H. METHODS-RESULTS: Compared with the wild-type hGRalpha, the mutant receptor hGRalphaD401H demonstrated a 2.4-fold increase in its ability to transactivate the glucocorticoid-inducible mouse mammary tumor virus promoter in response to dexamethasone but had similar affinity for the ligand (dissociation constant = 6.2 +/- 0.6 vs. 6.1 +/- 0.6 nm) and time to nuclear translocation (14.75 +/- 0.25 vs. 14.25 +/- 1.13 min). The mutant receptor hGRalphaD401H did not exert a dominant positive or negative effect upon the wild-type receptor, it preserved its ability to bind to glucocorticoid response elements, and displayed a normal interaction with the glucocorticoid receptor-interacting protein 1 coactivator. CONCLUSIONS: The mutant receptor hGRalphaD401H enhances the transcriptional activity of glucocorticoid-responsive genes. The presence of the D401H mutation may predispose subjects to obesity, hypertension, and other manifestations of the metabolic syndrome."
],
"offsets": [
[
140,
1817
]
]
}
] | [
{
"id": "356",
"type": "DNAMutation",
"text": [
"(G --> C) substitution at position 1201"
],
"offsets": [
[
558,
597
]
],
"normalized": []
},
{
"id": "357",
"type": "ProteinMutation",
"text": [
"D401H"
],
"offsets": [
[
845,
850
]
],
"normalized": []
},
{
"id": "358",
"type": "ProteinMutation",
"text": [
"D401H"
],
"offsets": [
[
935,
940
]
],
"normalized": []
},
{
"id": "359",
"type": "ProteinMutation",
"text": [
"D401H"
],
"offsets": [
[
1299,
1304
]
],
"normalized": []
},
{
"id": "360",
"type": "ProteinMutation",
"text": [
"D401H"
],
"offsets": [
[
1601,
1606
]
],
"normalized": []
},
{
"id": "361",
"type": "ProteinMutation",
"text": [
"D401H"
],
"offsets": [
[
1701,
1706
]
],
"normalized": []
}
] | [] | [] | [] |
364 | 18813858 | [
{
"id": "367",
"type": "title",
"text": [
"Novel mutations in the IRF6 gene in Brazilian families with Van der Woude syndrome."
],
"offsets": [
[
0,
83
]
]
},
{
"id": "368",
"type": "abstract",
"text": [
"Van der Woude Syndrome (VWS) is an autosomal craniofacial disorder characterized by lower lip pits and cleft lip and/or palate. Mutations in the interferon regulatory factor 6 (IRF6) gene have been identified in patients with VWS. To identify novel IRF6 mutations in patients affected by VWS, we screened 2 Brazilian families, sequencing the entire IRF6-coding region and flanking intronic boundaries. Two novel heterozygous mutations were identified: a frame shift mutation with deletion of G at the nucleotide position 520 in the exon 6 (520delG), and a missense single nucleotide substitution from T to A at nucleotide position 1135 in exon 8 (T1135A). By using restriction enzyme analysis, we were able to demonstrate the lack of similar mutations in unrelated healthy individuals and non-syndromic cleft lip and palate patients. Our results further confirmed that haploinsufficiency of the IRF6 gene results in VWS."
],
"offsets": [
[
84,
1004
]
]
}
] | [
{
"id": "365",
"type": "DNAMutation",
"text": [
"520delG"
],
"offsets": [
[
624,
631
]
],
"normalized": []
},
{
"id": "366",
"type": "DNAMutation",
"text": [
"T1135A"
],
"offsets": [
[
731,
737
]
],
"normalized": []
}
] | [] | [] | [] |
369 | 18806880 | [
{
"id": "373",
"type": "title",
"text": [
"Genetics of Meesmann corneal dystrophy: a novel mutation in the keratin 3 gene in an asymptomatic family suggests genotype-phenotype correlation."
],
"offsets": [
[
0,
145
]
]
},
{
"id": "374",
"type": "abstract",
"text": [
"PURPOSE: Juvenile epithelial corneal dystrophy of Meesmann (MCD, OMIM 122100) is a dominantly inherited disorder characterized by fragility of the anterior corneal epithelium and intraepithelial microcyst formation. Although the disease is generally mild and affected individuals are often asymptomatic, some suffer from recurrent erosions leading to lacrimation, photophobia, and deterioration in visual acuity. MCD is caused by mutations in keratin 3 (KRT3) or keratin 12 (KRT12) genes, which encode cornea-specific cytoskeletal proteins. Seventeen mutations in KRT12 and two in KRT3 have been described so far. The purpose of this study was to investigate the genetic background of MCD in a Polish family. METHODS: We report on a three-generation family with MCD. Epithelial lesions characteristic for MCD were visualized with slit-lamp examination and confirmed by in vivo confocal microscopy. Using genomic DNA as a template, all coding regions of KRT3 and KRT12 were amplified and sequenced. Presence of the mutation was verified with restriction endonuclease digestion. RESULTS: In the proband, direct sequencing of the polymerase chain reaction (PCR) product from amplified coding regions of KRT3 and KRT12 revealed a novel 1493A>T heterozygous missense mutation in exon 7 of KRT3, which predicts the substitution of glutamic acid for valine at codon 498 (E498V). Using PCR-Restriction Fragment Length Polymorphism (RFLP) analysis, the mutation was demonstrated to segregate with the disease (four affected members, three non-affected) and to be absent in 100 controls from the Polish population, indicating that it is not a common polymorphism. CONCLUSIONS: Location of the E498V mutation emphasizes the functional relevance of the highly conserved boundary motifs at the COOH-terminus of the alpha-helical rod domain in keratin 3 (K3)."
],
"offsets": [
[
146,
1991
]
]
}
] | [
{
"id": "370",
"type": "DNAMutation",
"text": [
"1493A>T"
],
"offsets": [
[
1378,
1385
]
],
"normalized": []
},
{
"id": "371",
"type": "ProteinMutation",
"text": [
"E498V"
],
"offsets": [
[
1510,
1515
]
],
"normalized": []
},
{
"id": "372",
"type": "ProteinMutation",
"text": [
"E498V"
],
"offsets": [
[
1829,
1834
]
],
"normalized": []
}
] | [] | [] | [] |
375 | 18779591 | [
{
"id": "379",
"type": "title",
"text": [
"Identification of a gain-of-function mutation of the prolactin receptor in women with benign breast tumors."
],
"offsets": [
[
0,
107
]
]
},
{
"id": "380",
"type": "abstract",
"text": [
"There is currently no known genetic disease linked to prolactin (Prl) or its receptor (PrlR) in humans. Given the essential role of this hormonal system in breast physiology, we reasoned that genetic anomalies of Prl/PrlR genes may be related to the occurrence of breast diseases with high proliferative potential. Multiple fibroadenomas (MFA) are benign breast tumors which appear most frequently in young women, including at puberty, when Prl has well-recognized proliferative actions on the breast. In a prospective study involving 74 MFA patients and 170 control subjects, we identified four patients harboring a heterozygous single nucleotide polymorphism in exon 6 of the PrlR gene, encoding Ile(146)-->Leu substitution in its extracellular domain. This sole substitution was sufficient to confer constitutive activity to the receptor variant (PrlR(I146L)), as assessed in three reconstituted cell models (Ba/F3, HEK293 and MCF-7 cells) by Prl-independent (i) PrlR tyrosine phosphorylation, (ii) activation of signal transducer and activator of transcription 5 (STAT5) signaling, (iii) transcriptional activity toward a Prl-responsive reporter gene, and (iv) cell proliferation and protection from cell death. Constitutive activity of PrlR(I146L) in the breast sample from a patient was supported by increased STAT5 signaling. This is a unique description of a functional mutation of the PrlR associated with a human disease. Hallmarks of constitutive activity were all reversed by a specific PrlR antagonist, which opens potential therapeutic approaches for MFA, or any other disease that could be associated with this mutation in future."
],
"offsets": [
[
108,
1753
]
]
}
] | [
{
"id": "376",
"type": "ProteinMutation",
"text": [
"Ile(146)-->Leu"
],
"offsets": [
[
806,
820
]
],
"normalized": []
},
{
"id": "377",
"type": "ProteinMutation",
"text": [
"I146L"
],
"offsets": [
[
963,
968
]
],
"normalized": []
},
{
"id": "378",
"type": "ProteinMutation",
"text": [
"I146L"
],
"offsets": [
[
1354,
1359
]
],
"normalized": []
}
] | [] | [] | [] |
381 | 18704161 | [
{
"id": "382",
"type": "title",
"text": [
"Genetic variation in an individual human exome."
],
"offsets": [
[
0,
47
]
]
},
{
"id": "383",
"type": "abstract",
"text": [
"There is much interest in characterizing the variation in a human individual, because this may elucidate what contributes significantly to a person's phenotype, thereby enabling personalized genomics. We focus here on the variants in a person's 'exome,' which is the set of exons in a genome, because the exome is believed to harbor much of the functional variation. We provide an analysis of the approximately 12,500 variants that affect the protein coding portion of an individual's genome. We identified approximately 10,400 nonsynonymous single nucleotide polymorphisms (nsSNPs) in this individual, of which approximately 15-20% are rare in the human population. We predict approximately 1,500 nsSNPs affect protein function and these tend be heterozygous, rare, or novel. Of the approximately 700 coding indels, approximately half tend to have lengths that are a multiple of three, which causes insertions/deletions of amino acids in the corresponding protein, rather than introducing frameshifts. Coding indels also occur frequently at the termini of genes, so even if an indel causes a frameshift, an alternative start or stop site in the gene can still be used to make a functional protein. In summary, we reduced the set of approximately 12,500 nonsilent coding variants by approximately 8-fold to a set of variants that are most likely to have major effects on their proteins' functions. This is our first glimpse of an individual's exome and a snapshot of the current state of personalized genomics. The majority of coding variants in this individual are common and appear to be functionally neutral. Our results also indicate that some variants can be used to improve the current NCBI human reference genome. As more genomes are sequenced, many rare variants and non-SNP variants will be discovered. We present an approach to analyze the coding variation in humans by proposing multiple bioinformatic methods to hone in on possible functional variation."
],
"offsets": [
[
48,
2013
]
]
}
] | [] | [] | [] | [] |
384 | 18398821 | [
{
"id": "385",
"type": "title",
"text": [
"Genome-wide analysis identifies 16q deletion associated with survival, molecular subtypes, mRNA expression, and germline haplotypes in breast cancer patients."
],
"offsets": [
[
0,
158
]
]
},
{
"id": "386",
"type": "abstract",
"text": [
"Breast carcinomas are characterized by DNA copy number alterations (CNAs) with biological and clinical significance. This explorative study integrated CNA, expression, and germline genotype data of 112 early-stage breast cancer patients. Recurrent CNAs differed substantially between tumor subtypes classified according to expression pattern. Deletion of 16q was overrepresented in Luminal A, and a predictor of good prognosis, both overall and for the nonluminal A subgroups. The deleted region most significantly associated with survival mapped to 16q22.2, harboring the genes TXNL4B and DXH38, whose expression was strongly correlated with the deletion. The area most frequently deleted resided on 16q23.1, 3.5 MB downstream of the area most significantly associated with survival, and included the tumor suppressor gene ADAMTS18 and the cell recognition gene CNTNAP4. Whole-genome association analysis identified germline single nucleotide polymorphisms (SNPs) and their corresponding haplotypes, residing on several different chromosomes, to be associated with deletion of 16q. The genes where these SNPs reside encode proteins involved in the extracellular matrix (CHST3 and SPOCK2), in regulation of the cell cycle (JMY, PTPRN2, and Cwf19L2) and chromosome stability (KPNB1)."
],
"offsets": [
[
159,
1441
]
]
}
] | [] | [] | [] | [] |
387 | 18385169 | [
{
"id": "392",
"type": "title",
"text": [
"TNFA -308G>A in two international population-based cohorts and risk of asthma."
],
"offsets": [
[
0,
78
]
]
},
{
"id": "393",
"type": "abstract",
"text": [
"Genetic association studies have related the tumour necrosis factor-alpha gene (TNFA) guanine to adenine substitution of nucleotide -308 (-308G>A) polymorphism to increased risk of asthma, but results are inconsistent. The aim of the present study was to test whether two single-nucleotide polymorphisms, of TNFA and of the lymphotoxin-alpha gene (LTA), are associated with asthma, bronchial hyperresponsiveness and atopy in adults, by combining the results of two large population-based multicentric studies and conducting a meta-analysis of previously published studies. The European Community Respiratory Health Survey (ECRHS) and Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) used comparable protocols, including questionnaires for respiratory symptoms and measures of lung function and atopy. DNA samples from 11,136 participants were genotyped at TNFA -308 and LTA 252. Logistic regression employing fixed and random effects models and nonparametric techniques were used. The prevalence of asthma was 6%. The TNFA -308G>A polymorphism was associated with increased asthma prevalence and with bronchial hyperresponsiveness. No consistent association was found for atopy. The LTA 252A>G polymorphism was not associated with any of the outcomes. A meta-analysis of 17 studies showed an increased asthma risk for the TNFA -308 adenine allele. The tumour necrosis factor-alpha gene nucleotide -308 polymorphism is associated with a moderately increased risk of asthma and bronchial hyperresponsiveness, but not with atopy. These results are supported by a meta-analysis of previously published studies."
],
"offsets": [
[
79,
1721
]
]
}
] | [
{
"id": "388",
"type": "DNAMutation",
"text": [
"-308G>A"
],
"offsets": [
[
5,
12
]
],
"normalized": []
},
{
"id": "389",
"type": "DNAMutation",
"text": [
"-308G>A"
],
"offsets": [
[
217,
224
]
],
"normalized": []
},
{
"id": "390",
"type": "DNAMutation",
"text": [
"-308G>A"
],
"offsets": [
[
1138,
1145
]
],
"normalized": []
},
{
"id": "391",
"type": "DNAMutation",
"text": [
"252A>G"
],
"offsets": [
[
1302,
1308
]
],
"normalized": []
}
] | [] | [] | [] |
394 | 18272172 | [
{
"id": "399",
"type": "title",
"text": [
"A splice site mutation in hERG leads to cryptic splicing in human long QT syndrome."
],
"offsets": [
[
0,
83
]
]
},
{
"id": "400",
"type": "abstract",
"text": [
"Mutations in the human ether-a-go-go-related gene (hERG) cause type 2 long QT syndrome. In this study, we investigated the pathogenic mechanism of the hERG splice site mutation 2398+1G>C and the genotype-phenotype relationship of mutation carriers in three unrelated kindreds with long QT syndrome. The effect of 2398+1G>C on mRNA splicing was studied by analysis of RNA isolated from lymphocytes of index patients and using minigenes expressed in HEK293 cells and neonatal rat ventricular myocytes. RT-PCR analysis revealed that the 2398+1G>C mutation disrupted the normal splicing and activated a cryptic splice donor site in intron 9, leading to the inclusion of 54 nt of the intron 9 sequence in hERG mRNA. The cryptic splicing resulted in an in-frame insertion of 18 amino acids in the middle of the cyclic nucleotide binding domain. In patch clamp experiments the splice mutant did not generate hERG current. Western blot and immunostaining studies showed that the mutant expressed an immature form of hERG protein that failed to reach the plasma membrane. Coexpression of the mutant and wild-type channels led to a dominant negative suppression of wild-type channel function by intracellular retention of heteromeric channels. Our results demonstrate that 2398+1G>C activates a cryptic site and generates a full-length hERG protein with an insertion of 18 amino acids, which leads to a trafficking defect of the mutant channel."
],
"offsets": [
[
84,
1518
]
]
}
] | [
{
"id": "395",
"type": "DNAMutation",
"text": [
"2398+1G>C"
],
"offsets": [
[
261,
270
]
],
"normalized": []
},
{
"id": "396",
"type": "DNAMutation",
"text": [
"2398+1G>C"
],
"offsets": [
[
397,
406
]
],
"normalized": []
},
{
"id": "397",
"type": "DNAMutation",
"text": [
"2398+1G>C"
],
"offsets": [
[
618,
627
]
],
"normalized": []
},
{
"id": "398",
"type": "DNAMutation",
"text": [
"2398+1G>C"
],
"offsets": [
[
1347,
1356
]
],
"normalized": []
}
] | [] | [] | [] |
401 | 18270997 | [
{
"id": "408",
"type": "title",
"text": [
"Catechol-O-methyltransferase (COMT) gene variants: possible association of the Val158Met variant with opiate addiction in Hispanic women."
],
"offsets": [
[
0,
137
]
]
},
{
"id": "409",
"type": "abstract",
"text": [
"Catechol-O-methyltransferase (COMT) catalyzes the breakdown of catechol neurotransmitters, including dopamine, which plays a prominent role in drug reward. A common single nucleotide polymorphism (SNP), G472A, codes for a Val158Met substitution and results in a fourfold down regulation of enzyme activity. We sequenced exon IV of COMT gene in search for novel polymorphisms and then genotyped four out of five identified by direct sequencing, using TaqMan assay on 266 opioid-dependent and 173 control subjects. Genotype frequencies of the G472A SNP varied significantly (P = 0.029) among the three main ethnic/cultural groups (Caucasians, Hispanics, and African Americans). Using a genotype test, we found a trend to point-wise association (P = 0.053) of the G472A SNP in Hispanic subjects with opiate addiction. Further analysis of G472A genotypes in Hispanic subjects with data stratified by gender identified a point-wise significant (P = 0.049) association of G/A and A/A genotypes with opiate addiction in women, but not men. These point-wise significant results are not significant experiment-wise (at P < 0.05) after correction for multiple testing. No significant association was found with haplotypes of the three most common SNPs. Linkage disequilibrium patterns were similar for the three ethnic/cultural groups."
],
"offsets": [
[
138,
1463
]
]
}
] | [
{
"id": "402",
"type": "ProteinMutation",
"text": [
"Val158Met"
],
"offsets": [
[
79,
88
]
],
"normalized": []
},
{
"id": "403",
"type": "DNAMutation",
"text": [
"G472A"
],
"offsets": [
[
341,
346
]
],
"normalized": []
},
{
"id": "404",
"type": "ProteinMutation",
"text": [
"Val158Met"
],
"offsets": [
[
360,
369
]
],
"normalized": []
},
{
"id": "405",
"type": "DNAMutation",
"text": [
"G472A"
],
"offsets": [
[
679,
684
]
],
"normalized": []
},
{
"id": "406",
"type": "DNAMutation",
"text": [
"G472A"
],
"offsets": [
[
899,
904
]
],
"normalized": []
},
{
"id": "407",
"type": "DNAMutation",
"text": [
"G472A"
],
"offsets": [
[
973,
978
]
],
"normalized": []
}
] | [] | [] | [] |
410 | 18266724 | [
{
"id": "413",
"type": "title",
"text": [
"Histamine-N-methyl transferase polymorphism and risk for migraine."
],
"offsets": [
[
0,
66
]
]
},
{
"id": "414",
"type": "abstract",
"text": [
"BACKGROUND/OBJECTIVES: Histamine has been implicated in the pathogenesis of migraine. In the CNS, histamine is almost exclusively metabolized by the polymorphic enzyme histamine N-methyltransferase (HNMT). The HNMT gene (chromosome 2q22.1), shows diverse single nucleotide polymorphisms. One of these, located in exon 4 C314T, causes the amino acid substitution Thr105Ile, related to decreased enzyme activity. The aim of this study was to investigate the possible association between HNMT polymorphism and the risk for migraine. METHODS: We studied the frequency of the HNMT genotypes and allelic variantes in 197 patients with migraine and 245 healthy controls using a PCR-RLFP method. RESULTS: The frequencies of the HNMT genotypes and allelic variants did not differ significantly between migraine patients and controls, and were unrelated with the age of onset of migraine attacks, gender, personal history of allergic diseases, family history of migraine, or presence of aura. CONCLUSION: The results of the present study suggest that HNMT polymorphism in not related with the risk for migraine."
],
"offsets": [
[
67,
1168
]
]
}
] | [
{
"id": "411",
"type": "DNAMutation",
"text": [
"C314T"
],
"offsets": [
[
387,
392
]
],
"normalized": []
},
{
"id": "412",
"type": "ProteinMutation",
"text": [
"Thr105Ile"
],
"offsets": [
[
429,
438
]
],
"normalized": []
}
] | [] | [] | [] |
415 | 18164595 | [
{
"id": "419",
"type": "title",
"text": [
"Mutations in the hairless gene underlie APL in three families of Pakistani origin."
],
"offsets": [
[
0,
82
]
]
},
{
"id": "420",
"type": "abstract",
"text": [
"BACKGROUND: Atrichia with papular lesions (APL) (OMIM#209500) is a rare autosomal recessively inherited form of irreversible alopecia characterized by papular lesions of keratin-filled cysts on various regions of the body. Males and females are equally affected and present with a distinct pattern of total hair loss on scalp, axilla and body. It begins shortly after birth with the development of hair loss, and patients are normally devoid of eyelashes and eyebrows. Mutations in the hairless (HR) gene have been previously shown to be responsible for APL. OBJECTIVE: In this study, we studied the molecular basis of APL in three unrelated families of Pakistani origin. METHOD: Molecular analysis of the HR genes was performed on genomic DNA from probands and family members. RESULTS: DNA sequencing of the HR gene in family A revealed a novel homozygous 2bp deletion in exon 6 leading to a frameshift and a downstream premature termination codon in exon 8 (1782-83delAG). In family B, we identified a novel homozygous deletion of a G nucleotide at the exon 15-intron 15 boundary, termed 3097delG. Family C carries a previously reported missense mutation consisting of an A-to-G transition at nucleotide 276 resulting in the mutation N970S in exon 14. CONCLUSION: Two mutations identified in this study are novel mutations in the HR gene and extend the body of evidence implicating the hairless gene family in the pathogenesis of human skin disorders. The one previously reported mutation suggests it may represent a recurrent mutation, or alternatively, an allele that is widely dispersed around the world."
],
"offsets": [
[
83,
1692
]
]
}
] | [
{
"id": "416",
"type": "DNAMutation",
"text": [
"1782-83delAG"
],
"offsets": [
[
1043,
1055
]
],
"normalized": []
},
{
"id": "417",
"type": "DNAMutation",
"text": [
"3097delG"
],
"offsets": [
[
1173,
1181
]
],
"normalized": []
},
{
"id": "418",
"type": "ProteinMutation",
"text": [
"N970S"
],
"offsets": [
[
1319,
1324
]
],
"normalized": []
}
] | [] | [] | [] |
421 | 18046082 | [
{
"id": "424",
"type": "title",
"text": [
"Identification of apolipoprotein E Guangzhou (arginine 150 proline), a new variant associated with lipoprotein glomerulopathy."
],
"offsets": [
[
0,
126
]
]
},
{
"id": "425",
"type": "abstract",
"text": [
"BACKGROUND/AIMS: Lipoprotein glomerulopathy (LPG) is a rare disease characterized by thrombus-like substances in markedly dilated glomerular capillaries and elevated plasma levels of apolipoprotein E (apoE). Previous studies have shown that genetic disorders of apoE may contribute to the pathogenesis of LPG, but LPG may not be caused by apoE gene mutations in Chinese patients. This study investigated the association of a new variant of apoE with LPG in a Chinese family. METHODS: The apoE gene in a family with 4 LPG patients was sequenced. The polymerase chain reaction product of coding region of apoE exon 4 was cloned into pMD 18-T vector and then sequenced. RESULTS: A novel point mutation in exon 4 of the apoE gene was identified in all 4 LPG patients and 1 asymptomatic family member. Sequence analysis confirmed a nucleotide G to C point mutation in exon 4 (base 308) of the apoE gene in all patients and the asymptomatic family member. This missense mutation denotes amino acid substitution of the proline residue for arginine residue at position 150 of apoE. Those patients were all heterozygotes with apoE Guangzhou. One of 2 grandsons was a heterozygous carrier of apoE Guangzhou, although he did not have proteinuria. CONCLUSION: The results of this study suggest that apoE (arginine 150 proline) is a novel apoE variant that etiologically related to LPG. This variant (apoE Guangzhou) may cause a marked molecular conformational change of the apoE and thus impair its binding ability to lipids."
],
"offsets": [
[
127,
1640
]
]
}
] | [
{
"id": "422",
"type": "ProteinMutation",
"text": [
"arginine 150 proline"
],
"offsets": [
[
46,
66
]
],
"normalized": []
},
{
"id": "423",
"type": "ProteinMutation",
"text": [
"arginine 150 proline"
],
"offsets": [
[
1420,
1440
]
],
"normalized": []
}
] | [] | [] | [] |
426 | 18036257 | [
{
"id": "427",
"type": "title",
"text": [
"Single nucleotide polymorphisms in bone turnover-related genes in Koreans: ethnic differences in linkage disequilibrium and haplotype."
],
"offsets": [
[
0,
134
]
]
},
{
"id": "428",
"type": "abstract",
"text": [
"BACKGROUND: Osteoporosis is defined as the loss of bone mineral density that leads to bone fragility with aging. Population-based case-control studies have identified polymorphisms in many candidate genes that have been associated with bone mass maintenance or osteoporotic fracture. To investigate single nucleotide polymorphisms (SNPs) that are associated with osteoporosis, we examined the genetic variation among Koreans by analyzing 81 genes according to their function in bone formation and resorption during bone remodeling. METHODS: We resequenced all the exons, splice junctions and promoter regions of candidate osteoporosis genes using 24 unrelated Korean individuals. Using the common SNPs from our study and the HapMap database, a statistical analysis of deviation in heterozygosity depicted. RESULTS: We identified 942 variants, including 888 SNPs, 43 insertion/deletion polymorphisms, and 11 microsatellite markers. Of the SNPs, 557 (63%) had been previously identified and 331 (37%) were newly discovered in the Korean population. When compared SNPs in the Korean population with those in HapMap database, 1% (or less) of SNPs in the Japanese and Chinese subpopulations and 20% of those in Caucasian and African subpopulations were significantly differentiated from the Hardy-Weinberg expectations. In addition, an analysis of the genetic diversity showed that there were no significant differences among Korean, Han Chinese and Japanese populations, but African and Caucasian populations were significantly differentiated in selected genes. Nevertheless, in the detailed analysis of genetic properties, the LD and Haplotype block patterns among the five sub-populations were substantially different from one another. CONCLUSION: Through the resequencing of 81 osteoporosis candidate genes, 118 unknown SNPs with a minor allele frequency (MAF) > 0.05 were discovered in the Korean population. In addition, using the common SNPs between our study and HapMap, an analysis of genetic diversity and deviation in heterozygosity was performed and the polymorphisms of the above genes among the five populations were substantially differentiated from one another. Further studies of osteoporosis could utilize the polymorphisms identified in our data since they may have important implications for the selection of highly informative SNPs for future association studies."
],
"offsets": [
[
135,
2514
]
]
}
] | [] | [] | [] | [] |
429 | 17962469 | [
{
"id": "430",
"type": "title",
"text": [
"Novel TULP1 mutation causing leber congenital amaurosis or early onset retinal degeneration."
],
"offsets": [
[
0,
92
]
]
},
{
"id": "431",
"type": "abstract",
"text": [
"PURPOSE: To report a large, consanguineous Algerian family affected with Leber congenital amaurosis (LCA) or early-onset retinal degeneration (EORD). METHODS: All accessible family members underwent a complete ophthalmic examination, and blood was obtained for DNA extraction. Homozygosity mapping was performed with markers flanking 12 loci associated with LCA. The 15 exons of TULP1 were sequenced. RESULTS: Seven of 30 examined family members were affected, including five with EORD and two with LCA. All patients had nystagmus, hemeralopia, mild myopia, and low visual acuity without photophobia. Fundus features were variable among EORD patients: typical spicular retinitis pigmentosa or clumped pigmented retinopathy with age-dependent macular involvement. A salt-and-pepper retinopathy with midperipheral retinal pigment epithelium (RPE) atrophy was present in the older patients with LCA, whereas the retina appeared virtually normal in the younger ones. Both scotopic and photopic electroretinograms were nondetectable. Fundus imaging revealed a perifoveal ring of increased fundus autofluorescence (FAF) in the proband, and optical coherence tomography disclosed a thinned retina, mainly due to photoreceptor loss. Linkage analysis identified a region of homozygosity on chromosome 6, region p21.3, and mutation screening revealed a novel 6-base in-frame duplication, in the TULP1 gene. CONCLUSIONS: Mutation in the TULP1 gene is a rare cause of LCA/EORD, with only 14 mutations reported so far. The observed intrafamilial phenotypic variability could be attributed to disease progression or possibly modifier alleles. This study provides the first description of FAF and quantitative reflectivity profiles in TULP1-related retinopathy."
],
"offsets": [
[
93,
1839
]
]
}
] | [] | [] | [] | [] |
432 | 17951029 | [
{
"id": "436",
"type": "title",
"text": [
"Focal dermal hypoplasia resulting from a new nonsense mutation, p.E300X, in the PORCN gene."
],
"offsets": [
[
0,
91
]
]
},
{
"id": "437",
"type": "abstract",
"text": [
"BACKGROUND: Focal dermal hypoplasia (FDH) (OMIM 305600) is an X-linked dominant disorder of ecto-mesodermal development. Also known as Goltz syndrome, FDH presents with characteristic linear streaks of hypoplastic dermis and variable abnormalities of bone, nails, hair, limbs, teeth and eyes. The molecular basis of FDH involves mutations in the PORCN gene, which encodes an enzyme that allows membrane targeting and secretion of several Wnt proteins critical for normal tissue development. OBJECTIVES: To investigate the molecular basis of FDH in a 2-year-old Thai girl who presented at birth with depressed, pale linear scars on the trunk and limbs, sparse brittle hair, syndactyly of the right middle and ring fingers, dental caries and radiological features of osteopathia striata. METHODS: Sequencing of genomic DNA from the affected individual and both parents to search for pathogenic mutations in PORCN gene. RESULTS: DNA sequencing disclosed a heterozygous G>T substitution at nucleotide c.898 within exon 10 (NM_203475.1), converting a glutamic acid residue (GAA) to a premature termination codon (TAA). This mutation, designated p.E300X, was not detected in DNA from either parent or in 100 control chromosomes. CONCLUSION: Identification of this new de novo nonsense mutation confirms the diagnosis of FDH in this child and highlights the clinical importance of PORCN and Wnt signalling pathways in embryogenesis."
],
"offsets": [
[
92,
1517
]
]
}
] | [
{
"id": "433",
"type": "ProteinMutation",
"text": [
"p.E300X"
],
"offsets": [
[
64,
71
]
],
"normalized": []
},
{
"id": "434",
"type": "DNAMutation",
"text": [
"G>T substitution at nucleotide c.898"
],
"offsets": [
[
1058,
1094
]
],
"normalized": []
},
{
"id": "435",
"type": "ProteinMutation",
"text": [
"p.E300X"
],
"offsets": [
[
1232,
1239
]
],
"normalized": []
}
] | [] | [] | [] |
438 | 17868390 | [
{
"id": "442",
"type": "title",
"text": [
"A novel DFNA5 mutation, IVS8+4 A>G, in the splice donor site of intron 8 causes late-onset non-syndromic hearing loss in a Chinese family."
],
"offsets": [
[
0,
138
]
]
},
{
"id": "443",
"type": "abstract",
"text": [
"We report here the clinical, genetic, and molecular characteristics of a large Chinese family exhibiting non-syndromic, late-onset autosomal dominant sensorineural hearing loss. Clinical evaluation revealed variable phenotypes of hearing loss in terms of severity and age-at-onset of disease in these subjects. Genome-wide linkage analysis mapped the disease gene to the DFNA5 locus with a maximum two-point log odds score of 5.39 at [theta] = 0 for marker D7S2457. DNA sequencing of DFNA5 revealed a novel heterozygous IVS8+4 A>G substitution in the splice donor site of intron 8. Reverse transcriptase-polymerase chain reaction (RT-PCR) showed skipping of exon 8 in the mutant transcript. This mutation faithfully cosegregated with hearing loss in the family. In addition, the mutation was absent in 100 unrelated control DNA samples of Chinese origin. The IVS8+4 A>G mutation is predicted to create a shift in the reading frame and introduce a stop codon at position 372, thereby resulting in a prematurely truncated DFNA5 protein. Up to date, a total of four mutations in DFNA5 have been reported to lead to hearing impairment, all of them result in skipping of exon 8 at the mRNA level. Our findings provide further support for the hypothesis that DFNA5-associated hearing loss is caused by a very specific gain-of-function mutation."
],
"offsets": [
[
139,
1477
]
]
}
] | [
{
"id": "439",
"type": "DNAMutation",
"text": [
"IVS8+4 A>G"
],
"offsets": [
[
24,
34
]
],
"normalized": []
},
{
"id": "440",
"type": "DNAMutation",
"text": [
"IVS8+4 A>G"
],
"offsets": [
[
659,
669
]
],
"normalized": []
},
{
"id": "441",
"type": "DNAMutation",
"text": [
"IVS8+4 A>G"
],
"offsets": [
[
998,
1008
]
],
"normalized": []
}
] | [] | [] | [] |
444 | 17635946 | [
{
"id": "448",
"type": "title",
"text": [
"A novel point mutation in helix 11 of the ligand-binding domain of the human glucocorticoid receptor gene causing generalized glucocorticoid resistance."
],
"offsets": [
[
0,
152
]
]
},
{
"id": "449",
"type": "abstract",
"text": [
"BACKGROUND: Generalized glucocorticoid resistance is a rare condition characterized by partial, end-organ insensitivity to glucocorticoids, compensatory elevations in adrenocorticotropic hormone and cortisol secretion, and increased production of adrenal steroids with androgenic and/or mineralocorticoid activity. We have identified a new case of glucocorticoid resistance caused by a novel mutation of the human glucocorticoid receptor (hGR) gene and studied the molecular mechanisms through which the mutant receptor impairs glucocorticoid signal transduction. METHODS AND RESULTS: We identified a novel, single, heterozygous nucleotide (T --> C) substitution at position 2209 (exon 9alpha) of the hGR gene, which resulted in phenylalanine (F) to leucine (L) substitution at amino acid position 737 within helix 11 of the ligand-binding domain of the protein. Compared with the wild-type receptor, the mutant receptor hGRalphaF737L demonstrated a significant ligand-exposure time-dependent decrease in its ability to transactivate the glucocorticoid-inducible mouse mammary tumor virus promoter in response to dexamethasone and displayed a 2-fold reduction in the affinity for ligand, a 12-fold delay in nuclear translocation, and an abnormal interaction with the glucocorticoid receptor-interacting protein 1 coactivator. The mutant receptor preserved its ability to bind to DNA and exerted a dominant-negative effect on the wild-type hGRalpha only after a short duration of exposure to the ligand. CONCLUSIONS: The mutant receptor hGRalphaF737L causes generalized glucocorticoid resistance because of decreased affinity for the ligand, marked delay in nuclear translocation, and/or abnormal interaction with the glucocorticoid receptor-interacting protein 1 coactivator. These findings confirm the importance of the C terminus of the ligand-binding domain of the receptor in conferring transactivational activity."
],
"offsets": [
[
153,
2071
]
]
}
] | [
{
"id": "445",
"type": "DNAMutation",
"text": [
"(T --> C) substitution at position 2209"
],
"offsets": [
[
793,
832
]
],
"normalized": []
},
{
"id": "446",
"type": "ProteinMutation",
"text": [
"F737L"
],
"offsets": [
[
1082,
1087
]
],
"normalized": []
},
{
"id": "447",
"type": "ProteinMutation",
"text": [
"F737L"
],
"offsets": [
[
1697,
1702
]
],
"normalized": []
}
] | [] | [] | [] |
450 | 17634480 | [
{
"id": "454",
"type": "title",
"text": [
"Common germline genetic variation in antioxidant defense genes and survival after diagnosis of breast cancer."
],
"offsets": [
[
0,
109
]
]
},
{
"id": "455",
"type": "abstract",
"text": [
"PURPOSE: The prognosis of breast cancer varies considerably among individuals, and inherited genetic factors may help explain this variability. Of particular interest are genes involved in defense against reactive oxygen species (ROS) because ROS are thought to cause DNA damage and contribute to the pathogenesis of cancer. PATIENTS AND METHODS: We examined associations between 54 polymorphisms that tag the known common variants (minor allele frequency > 0.05) in 10 genes involved in oxidative damage repair (CAT, SOD1, SOD2, GPX1, GPX4, GSR, TXN, TXN2, TXNRD1, and TXNRD2) and survival in 4,470 women with breast cancer. RESULTS: Two single nucleotide polymorphisms (SNPs) in GPX4 (rs713041 and rs757229) were associated with all-cause mortality even after adjusting for multiple hypothesis testing (adjusted P = .0041 and P = .0035). These SNPs are correlated with each other (r2 = 0.61). GPX4 rs713041 is located near the selenocysteine insertion sequence element in the GPX4 3' untranslated region, and the rare allele of this SNP is associated with an increased risk of death, with a hazard ratio of 1.27 per rare allele carried (95% CI, 1.13 to 11.43). This effect was not attenuated after adjusting for tumor stage, grade, or estrogen receptor status. We found that the common allele is preferentially expressed in normal lymphocytes, normal breast, and breast tumors compared with the rare allele, but there were no differences in total levels of GPX4 mRNA across genotypes. CONCLUSION: These data provide strong support for the hypothesis that common variation in GPX4 is associated with prognosis after a diagnosis of breast cancer."
],
"offsets": [
[
110,
1756
]
]
}
] | [
{
"id": "451",
"type": "SNP",
"text": [
"rs713041"
],
"offsets": [
[
797,
805
]
],
"normalized": []
},
{
"id": "452",
"type": "SNP",
"text": [
"rs757229"
],
"offsets": [
[
810,
818
]
],
"normalized": []
},
{
"id": "453",
"type": "SNP",
"text": [
"rs713041"
],
"offsets": [
[
1010,
1018
]
],
"normalized": []
}
] | [] | [] | [] |
456 | 17628794 | [
{
"id": "457",
"type": "title",
"text": [
"Manganese superoxide dismutase (Mn-SOD) gene polymorphisms in urolithiasis."
],
"offsets": [
[
0,
75
]
]
},
{
"id": "458",
"type": "abstract",
"text": [
"Polymorphism in manganese superoxide dismutase gene (Mn-SOD) is a new approach to identify its probable association with urolithiasis. Oxidative stress may be involved in the development of stone formation in the renal system. MnSOD is one of the primary enzymes that directly scavenges potential harmful oxidizing species. A valine (Val) to alanine (Ala) substitution at amino acid 16, occurring in the mitochondrial targeting sequence of the MnSOD gene, has been associated with an increase in urolithiasis risk. This study was conducted to investigate the association of MnSOD gene polymorphism with the risk of urolithiasis. We investigated the MnSOD in 66 stone-forming adults and 72 healthy volunteers. DNA was isolated from peripheral blood and genotyping was performed with PCR-based methods. Then PCR products were cut by BsaW1. Products were run on 3% agarose gel, 246 bp regions were 1-Ala-9, 164 and 82 bp products were determined as 2 Val-9. Chi-square test was used for comparison between patients and controls. In the control group the homozygote Ala allele was significantly higher than in the patient group (P < 0.01). The distribution of Ala/Val and homozygote Val alleles in the patient group was significantly higher than in the control group (P < 0.05). MnSOD genotype determination may provide a tool to identify individuals who are at risk of urolithiasis. This experiment also provides data about antioxidant status and stone formation."
],
"offsets": [
[
76,
1536
]
]
}
] | [] | [] | [] | [] |
459 | 17615540 | [
{
"id": "463",
"type": "title",
"text": [
"A novel \"pearl box\" cataract associated with a mutation in the connexin 46 (GJA3) gene."
],
"offsets": [
[
0,
87
]
]
},
{
"id": "464",
"type": "abstract",
"text": [
"PURPOSE: To undertake mutation screening in the connexin 46 (GJA3) gene in seven congenital cataract families of Indian origin. METHODS: Seven Indian families with congenital cataract were analyzed by detailed family history and clinical evaluation. Each family had two to five affected members. Mutation screening was carried out in the candidate gene, connexin 46 (GJA3), using bidirectional sequencing of amplified products. Segregation of the observed change with the disease phenotype was further tested by restriction fragment length polymorphism (RFLP). RESULTS: Sequencing of the coding region of GJA3 showed the presence of a novel, heterozygous C260T change in one family (CC-472) who had two affected members. The cataract phenotype gave the appearance like a \"pearl box\" in these two affected individuals of this family. The observed C260T substitution created a novel restriction enzyme site for NlaIII and resulted in substitution of highly conserved threonine at position 87 by methionine (T87M). NlaIII restriction digestion analysis revealed this nucleotide change was not in unaffected members of this family or in 100 unrelated control subjects (200 chromosomes) with the same ethnic background. CONCLUSIONS: This is a novel mutation identified in the second transmembrane domain of the connexin 46. These findings thus expand the mutation spectrum of the GJA3 in association with congenital cataract."
],
"offsets": [
[
88,
1508
]
]
}
] | [
{
"id": "460",
"type": "DNAMutation",
"text": [
"C260T"
],
"offsets": [
[
743,
748
]
],
"normalized": []
},
{
"id": "461",
"type": "DNAMutation",
"text": [
"C260T"
],
"offsets": [
[
934,
939
]
],
"normalized": []
},
{
"id": "462",
"type": "ProteinMutation",
"text": [
"T87M"
],
"offsets": [
[
1093,
1097
]
],
"normalized": []
}
] | [] | [] | [] |
465 | 17595233 | [
{
"id": "468",
"type": "title",
"text": [
"Mutations in pattern recognition receptor genes modulate seroreactivity to microbial antigens in patients with inflammatory bowel disease."
],
"offsets": [
[
0,
138
]
]
},
{
"id": "469",
"type": "abstract",
"text": [
"BACKGROUND AND AIMS: A number of antibodies against microbial epitopes or self-antigens have been associated with Crohn's disease. The development of antibodies reflects a loss of tolerance to intestinal bacteria that underlies Crohn's disease, resulting in an exaggerated adaptive immune response to these bacteria. It was hypothesised that the development of antimicrobial antibodies is influenced by the presence of genetic variants in pattern recognition receptor genes. The aim of this study was therefore to investigate the influence of mutations in these innate immune receptor genes (nucleotide oligomerisation domain (NOD) 2/caspase recruitment domain (CARD) 15, NOD1/CARD4, TUCAN/CARDINAL/CARD8, Toll-like receptor (TLR) 4, TLR2, TLR1 and TLR6) on the development of antimicrobial and antiglycan antibodies in inflammatory bowel disease (IBD). Materials and METHODS: A cohort of 1163 unrelated patients with IBD (874 Crohn's disease, 259 ulcerative colitis, 30 indeterminate colitis) and 312 controls were analysed for anti-Saccharomyces cerevisiae antibodies (gASCA) IgG, anti-laminaribioside antibodies (ALCA) IgG, anti-chitobioside antibodies (ACCA) IgA, anti-mannobioside antibodies (AMCA) IgG and outer membrane porin (Omp) IgA and were genotyped for variants in NOD2/CARD15, TUCAN/CARDINAL/CARD8, NOD1/CARD4, TLR4, TLR1, TLR2 and TLR6. RESULTS: When compared with Crohn's disease patients without CARD15 mutations, the presence of at least one CARD15 variant in Crohn's disease patients more frequently led to gASCA positivity (66.1% versus 51.5%, p < 0.0001) and ALCA positivity (43.3% versus 34.9%, p = 0.018) and higher gASCA titers (85.7 versus 51.8 ELISA units, p < 0.0001), independent of ileal involvement. A gene dosage effect, with increasing gASCA and ALCA positivity for patients carrying none, one and two CARD15 variants, respectively, was seen for both markers. Similarly, Crohn's disease patients carrying NOD1/CARD4 indel had a higher prevalence of gASCA antibodies than wild-type patients (63.8% versus 55.2%, p = 0.014), also with a gene dosage effect. An opposite effect was observed for the TLR4 D299G and TLR2 P631H variants, with a lower prevalence of ACCA antibodies (23.4% versus 35%, p = 0.013) and Omp antibodies (20.5% versus 34.6%, p = 0.009), respectively. CONCLUSION: Variants in innate immune receptor genes were found to influence antibody formation against microbial epitopes. In this respect, it is intriguing that an opposite effect of CARD15 and TLR4 variants was observed. These findings may contribute to an understanding of the aetiology of the seroreactivity observed in IBD."
],
"offsets": [
[
139,
2770
]
]
}
] | [
{
"id": "466",
"type": "ProteinMutation",
"text": [
"D299G"
],
"offsets": [
[
2271,
2276
]
],
"normalized": []
},
{
"id": "467",
"type": "ProteinMutation",
"text": [
"P631H"
],
"offsets": [
[
2286,
2291
]
],
"normalized": []
}
] | [] | [] | [] |
470 | 17495183 | [
{
"id": "480",
"type": "title",
"text": [
"Tenomodulin is associated with obesity and diabetes risk: the Finnish diabetes prevention study."
],
"offsets": [
[
0,
96
]
]
},
{
"id": "481",
"type": "abstract",
"text": [
"We recently showed that long-term weight reduction changes the gene expression profile of adipose tissue in overweight individuals with impaired glucose tolerance (IGT). One of the responding genes was X-chromosomal tenomodulin (TNMD), a putative angiogenesis inhibitor. Our aim was to study the associations of individual single nucleotide polymorphisms and haplotypes with adiposity, glucose metabolism, and the risk of type 2 diabetes (T2D). Seven single nucleotide polymorphisms from two different haploblocks were genotyped from 507 participants of the Finnish Diabetes Prevention Study (DPS). Sex-specific genotype effects were observed. Three markers of haploblock 1 were associated with features of adiposity in women (rs5966709, rs4828037) and men (rs11798018). Markers rs2073163 and rs1155794 from haploblock 2 were associated with 2-hour plasma glucose levels in men during the 3-year follow-up. The same two markers together with rs2073162 associated with the conversion of IGT to T2D in men. The risk of developing T2D was approximately 2-fold in individuals with genotypes associated with higher 2-hour plasma glucose levels; the hazard ratios were 2.192 (p = 0.025) for rs2073162-A, 2.191 (p = 0.027) for rs2073163-C, and 1.998 (p = 0.054) for rs1155974-T. These results suggest that TNMD polymorphisms are associated with adiposity and also with glucose metabolism and conversion from IGT to T2D in men."
],
"offsets": [
[
97,
1516
]
]
}
] | [
{
"id": "471",
"type": "SNP",
"text": [
"rs5966709"
],
"offsets": [
[
824,
833
]
],
"normalized": []
},
{
"id": "472",
"type": "SNP",
"text": [
"rs4828037"
],
"offsets": [
[
835,
844
]
],
"normalized": []
},
{
"id": "473",
"type": "SNP",
"text": [
"rs11798018"
],
"offsets": [
[
855,
865
]
],
"normalized": []
},
{
"id": "474",
"type": "SNP",
"text": [
"rs2073163"
],
"offsets": [
[
876,
885
]
],
"normalized": []
},
{
"id": "475",
"type": "SNP",
"text": [
"rs1155794"
],
"offsets": [
[
890,
899
]
],
"normalized": []
},
{
"id": "476",
"type": "SNP",
"text": [
"rs2073162"
],
"offsets": [
[
1039,
1048
]
],
"normalized": []
},
{
"id": "477",
"type": "SNP",
"text": [
"rs2073162"
],
"offsets": [
[
1282,
1291
]
],
"normalized": []
},
{
"id": "478",
"type": "SNP",
"text": [
"rs2073163"
],
"offsets": [
[
1317,
1326
]
],
"normalized": []
},
{
"id": "479",
"type": "SNP",
"text": [
"rs1155974"
],
"offsets": [
[
1356,
1365
]
],
"normalized": []
}
] | [] | [] | [] |
482 | 17437275 | [
{
"id": "483",
"type": "title",
"text": [
"Novel mutations in the ZEB1 gene identified in Czech and British patients with posterior polymorphous corneal dystrophy."
],
"offsets": [
[
0,
120
]
]
},
{
"id": "484",
"type": "abstract",
"text": [
"We describe the search for mutations in six unrelated Czech and four unrelated British families with posterior polymorphous corneal dystrophy (PPCD); a relatively rare eye disorder. Coding exons and intron/exon boundaries of all three genes (VSX1, COL8A2, and ZEB1/TCF8) previously reported to be implicated in the pathogenesis of this disorder were screened by DNA sequencing. Four novel pathogenic mutations were identified in four families; two deletions, one nonsense, and one duplication within exon 7 in the ZEB1 gene located at 10p11.2. We also genotyped the Czech patients to test for a founder haplotype and lack of disease segregation with the 20p11.2 locus we previously described. Although a systematic clinical examination was not performed, our investigation does not support an association between ZEB1 changes and self reported non-ocular anomalies. In the remaining six families no disease causing mutations were identified thereby indicating that as yet unidentified gene(s) are likely to be responsible for PPCD."
],
"offsets": [
[
121,
1152
]
]
}
] | [] | [] | [] | [] |
485 | 17426470 | [
{
"id": "486",
"type": "title",
"text": [
"3' Mutation of the APC gene and family history of FAP in a patient with apparently sporadic desmoid tumors."
],
"offsets": [
[
0,
107
]
]
},
{
"id": "487",
"type": "abstract",
"text": [
"Desmoid tumors may occur sporadically or as part of the extraintestinal manifestations of familial adenomatous polyposis. Different phenotypes have been described and some genotype-phenotype correlations have been raised, associated with different sites of germline mutations in the adenomatous polyposis coli (APC) gene. We report on a 42-year-old woman ascertained for a large desmoid tumor of the anterior chest wall with pleural involvement, which persistently recurred despite a decade of treatment including hormone therapy, chemotherapy, and surgery. Spontaneous disappearance of the tumor was later noted after 1 year without any treatment and confirmed after 4 years of regular follow-up. Repeated colonoscopies were normal in the proband and DNA sequencing showed a frameshift mutation due to a single adenosine deletion at position 5772 (codon 1924). This mutation, located in the exon 15 at the 3' end of the APC gene, leads to an unusual and late onset phenotype. The pedigree revealed other isolated or familial adenomatous polyposis-associated cases of desmoid tumors. This family report shows that a molecular analysis of the APC gene should be performed in familial desmoid tumors for accurate genetic counseling and follow-up."
],
"offsets": [
[
108,
1352
]
]
}
] | [] | [] | [] | [] |
488 | 17372760 | [
{
"id": "491",
"type": "title",
"text": [
"Atypical Rothmund-Thomson syndrome in a patient with compound heterozygous mutations in RECQL4 gene and phenotypic features in RECQL4 syndromes."
],
"offsets": [
[
0,
144
]
]
},
{
"id": "492",
"type": "abstract",
"text": [
"We describe the natural history of the RTSII phenotype in a 7-year-old boy who developed intrauterine and postnatal growth retardation, failure to thrive and persisting diarrhoea. The growth hormone stimulation test identified an isolated growth hormone deficiency. Since infancy, the patient manifested skin lesions characterized by a very mild poikilodermic-like appearance on the cheeks only, widespread caf -au-lait spots and the absence of eyebrows and eyelashes. There was no cataract. Orthopaedic and radiologic work-up identified the absence of thumb anomaly and radial head luxation and patellar hypoplasia. Neurologic, cognitive milestones and intelligence were normal. The cytogenetic work-up did not show any anomaly. Based on this clinical presentation, we carried out a sequencing analysis of the RECQL4 gene, which is responsible for Rothmund-Thomson, RAPADILINO and Baller-Gerold syndromes and found a splice site mutation (IVS10-1G>A) and a nucleotide substitution in exon 12 (L638P). The mother was identified as a carrier for the substitution in exon 12 and the father for the splice site mutation, respectively. An analysis of the transcripts focused on the RECQL4 helicase domain: in the proband only those generated from the maternal L638 allele were present. This case report emphasizes the clinical overlap between RAPADILINO and Rothmund-Thomson syndromes within a continuum phenotypic spectrum. The distinctive set of clinical signs displayed by the patient may be accounted for by his unique combination of two different RECQL4 mutations. The molecular findings provide information that enhances our comprehension of genotype-phenotype correlations in RECQL4 diseases, enables a more precise genetic counseling to the parents and facilitates a more appropriate long-term follow-up to the affected child."
],
"offsets": [
[
145,
1976
]
]
}
] | [
{
"id": "489",
"type": "DNAMutation",
"text": [
"IVS10-1G>A"
],
"offsets": [
[
1086,
1096
]
],
"normalized": []
},
{
"id": "490",
"type": "ProteinMutation",
"text": [
"L638P"
],
"offsets": [
[
1140,
1145
]
],
"normalized": []
}
] | [] | [] | [] |
493 | 17327916 | [
{
"id": "494",
"type": "title",
"text": [
"Genome-wide analysis of neuroblastomas using high-density single nucleotide polymorphism arrays."
],
"offsets": [
[
0,
96
]
]
},
{
"id": "495",
"type": "abstract",
"text": [
"BACKGROUND: Neuroblastomas are characterized by chromosomal alterations with biological and clinical significance. We analyzed paired blood and primary tumor samples from 22 children with high-risk neuroblastoma for loss of heterozygosity (LOH) and DNA copy number change using the Affymetrix 10K single nucleotide polymorphism (SNP) array. FINDINGS: Multiple areas of LOH and copy number gain were seen. The most commonly observed area of LOH was on chromosome arm 11q (15/22 samples; 68%). Chromosome 11q LOH was highly associated with occurrence of chromosome 3p LOH: 9 of the 15 samples with 11q LOH had concomitant 3p LOH (P = 0.016). Chromosome 1p LOH was seen in one-third of cases. LOH events on chromosomes 11q and 1p were generally accompanied by copy number loss, indicating hemizygous deletion within these regions. The one exception was on chromosome 11p, where LOH in all four cases was accompanied by normal copy number or diploidy, implying uniparental disomy. Gain of copy number was most frequently observed on chromosome arm 17q (21/22 samples; 95%) and was associated with allelic imbalance in six samples. Amplification of MYCN was also noted, and also amplification of a second gene, ALK, in a single case. CONCLUSIONS: This analysis demonstrates the power of SNP arrays for high-resolution determination of LOH and DNA copy number change in neuroblastoma, a tumor in which specific allelic changes drive clinical outcome and selection of therapy."
],
"offsets": [
[
97,
1566
]
]
}
] | [] | [] | [] | [] |
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Dataset Card for tmVar v1
This dataset contains 500 PubMed articles manually annotated with mutation mentions of various kinds. It can be used for NER tasks only. The dataset is split into train(334) and test(166) splits
Citation Information
@article{wei2013tmvar,
title={tmVar: a text mining approach for extracting sequence variants in biomedical literature},
author={Wei, Chih-Hsuan and Harris, Bethany R and Kao, Hung-Yu and Lu, Zhiyong},
journal={Bioinformatics},
volume={29},
number={11},
pages={1433--1439},
year={2013},
publisher={Oxford University Press}
}
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