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BigScience Biomedical Datasets 114

[ { "id": "1764", "type": "title", "text": [ "Severe form of thyroid hormone resistance in a patient with homozygous/hemizygous mutation of T3 receptor gene." ], "offsets": [ [ 0, 111 ] ] }, { "id": "1765", "type": "abstract", "text": [ "Resistance to thyroid hormone syndrome (RTH) is a rare disorder, usually inherited as an autosomal dominant trait. Patients with RTH are usually euthyroid but can occasionally present with signs and symptoms of thyrotoxicosis or rarely with hypothyroidism. Affected individuals are usually heterozygous for mutations in the thyroid hormone receptor beta gene (TR-beta). We present a patient with RTH found to be homo-/hemizygous for a mutation in the TR-beta gene. The single nucleotide substitution I280S (1123T-->G) was present either on both alleles or in a hemizygous form with complete deletion of the second allele. The I280S mutation was recently reported in a heterozygous patient. The severe phenotype with seriously impaired intellectual development, hyperkinetic behaviour, tachycardia, hearing and visual impairment is probably due to the dominant negative effect of the I280S mutant protein and the absence of any functional TR-beta." ], "offsets": [ [ 112, 1058 ] ] } ]

[ { "id": "1760", "type": "ProteinMutation", "text": [ "I280S" ], "offsets": [ [ 612, 617 ] ], "normalized": [] }, { "id": "1761", "type": "DNAMutation", "text": [ "1123T-->G" ], "offsets": [ [ 619, 628 ] ], "normalized": [] }, { "id": "1762", "type": "ProteinMutation", "text": [ "I280S" ], "offsets": [ [ 738, 743 ] ], "normalized": [] }, { "id": "1763", "type": "ProteinMutation", "text": [ "I280S" ], "offsets": [ [ 995, 1000 ] ], "normalized": [] } ]

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[ { "id": "1767", "type": "title", "text": [ "Microevolution between paired antral and paired antrum and corpus Helicobacter pylori isolates recovered from individual patients." ], "offsets": [ [ 0, 130 ] ] }, { "id": "1768", "type": "abstract", "text": [ "Sequence variations located at the signal sequence and mid-region within the vacA gene, the 3'-end of the cagA gene, the indel motifs at the 3'-end of the cag pathogenicity island and the regions upstream of the vacA and ribA genes were determined by PCR in 19 paired antral or antrum and corpus Helicobacter pylori isolates obtained at the same endoscopic session, and three antral pairs taken sequentially. Random amplification of polymorphic DNA (RAPD)-PCR and fluorescent amplified fragment length polymorphism (FAFLP)-PCR fingerprinting were applied to these paired clinical isolates. The FAFLP-PCR profiles generated were phylogenetically analysed. For the 22 paired isolates there were no differences within pairs at five of the genetic loci studied. However, six pairs of isolates (27%), of which four were antrum and corpus pairs, showed differences in the numbers of repeats located at the 3'-end of the cagA gene. RAPD-PCR fingerprinting showed that 16 (73%) pairs, nine of which were antrum and corpus pairs, possessed identical profiles, while six (27%) displayed distinctly different profiles, indicating mixed infections. Three of the six pairs showing differences at the 3'-end of the cagA gene yielded identical RAPD-PCR fingerprints. FAFLP-PCR fingerprinting and phylogenetic analysis revealed that all 16 pairs that displayed identical RAPD-PCR profiles had highly similar, but not identical, fingerprints, demonstrating that these pairs were ancestrally related but had undergone minor genomic alterations. Two antrum and corpus pairs of isolates, within the latter group, were isolates obtained from two siblings from the same family. This analysis demonstrated that each sibling was colonized by ancestrally related strains that exhibited differences in vacA genotype characteristics." ], "offsets": [ [ 131, 1937 ] ] } ]

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[ { "id": "1773", "type": "title", "text": [ "A novel arginine substitution mutation in 1A domain and a novel 27 bp insertion mutation in 2B domain of keratin 12 gene associated with Meesmann's corneal dystrophy." ], "offsets": [ [ 0, 166 ] ] }, { "id": "1774", "type": "abstract", "text": [ "AIM: To determine the disease causing gene defects in two patients with Meesmann's corneal dystrophy. METHODS: Mutational analysis of domains 1A and 2B of the keratin 3 (K3) and keratin 12 (K12) genes from two patients with Meesmann's corneal dystrophy was performed by polymerase chain reaction amplification and direct sequencing. RESULTS: Novel mutations of the K12 gene were identified in both patients. In one patient a heterozygous point mutation (429A-->C = Arg135Ser) was found in the 1A domain of the K12 gene. This mutation was confirmed by restriction digestion. In the second patient a heterozygous 27 bp duplication was found inserted in the 2B domain at nucleotide position 1222 (1222ins27) of the K12 gene. This mutation was confirmed by gel electrophoresis. The mutations were not present in unaffected controls. CONCLUSION: Novel K12 mutations were linked to Meesmann's corneal dystrophy in two different patients. A missense mutation replacing a highly conserved arginine residue in the beginning of the helix initiation motif was found in one patient, and an insertion mutation, consisting of a duplication of 27 nucleotides, was found before the helix termination motif in the other." ], "offsets": [ [ 167, 1370 ] ] } ]

[ { "id": "1770", "type": "DNAMutation", "text": [ "429A-->C" ], "offsets": [ [ 621, 629 ] ], "normalized": [] }, { "id": "1771", "type": "ProteinMutation", "text": [ "Arg135Ser" ], "offsets": [ [ 632, 641 ] ], "normalized": [] }, { "id": "1772", "type": "DNAMutation", "text": [ "1222ins27" ], "offsets": [ [ 861, 870 ] ], "normalized": [] } ]

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[ { "id": "1787", "type": "title", "text": [ "A new but frequent mutation of apoB-100-apoB His3543Tyr." ], "offsets": [ [ 0, 56 ] ] }, { "id": "1788", "type": "abstract", "text": [ "ApolipoproteinB 100 (apoB-100) is an important component of atherogenic lipoproteins such as LDL and serves as a ligand for the LDL-receptor. Familial defective apolipoproteinB 100 (FDB) is caused by a R3500Q mutation of the apoB gene and results in decreased binding of LDL to the LDL-receptor. So far FDB is the most frequent and best studied alteration of apoB-100. Apart from this, three other apoB mutations, R3500W, R3531C and R3480W, affecting binding to the LDL-receptor are known to date. We screened the apoB gene segment of codons 3448-3561 by denaturing gradient gel electrophoresis (DGGE) analysis in a total of 853 consecutively sampled German patients undergoing diagnostic coronary angiography for suspected CAD. By this, a new single base mutation was detected and confirmed by DNA sequencing. The mutation, CAC(3543)TAC results in a His3543Tyr substitution in apoB-100 (H3543Y). The prevalence of heterozygotes for H3543Y in the study population was 0.47% compared to 0.12% for the known Arg 3500 Gln (R3500Q) mutation. In conclusion, the new mutation is four times more frequent than \"classical\" FDB and thus appears to be the most common apoB mutation in Germany." ], "offsets": [ [ 57, 1240 ] ] } ]

[ { "id": "1776", "type": "ProteinMutation", "text": [ "His3543Tyr" ], "offsets": [ [ 45, 55 ] ], "normalized": [] }, { "id": "1777", "type": "ProteinMutation", "text": [ "R3500Q" ], "offsets": [ [ 259, 265 ] ], "normalized": [] }, { "id": "1778", "type": "ProteinMutation", "text": [ "R3500W" ], "offsets": [ [ 471, 477 ] ], "normalized": [] }, { "id": "1779", "type": "ProteinMutation", "text": [ "R3531C" ], "offsets": [ [ 479, 485 ] ], "normalized": [] }, { "id": "1780", "type": "ProteinMutation", "text": [ "R3480W" ], "offsets": [ [ 490, 496 ] ], "normalized": [] }, { "id": "1781", "type": "DNAMutation", "text": [ "CAC(3543)TAC" ], "offsets": [ [ 882, 894 ] ], "normalized": [] }, { "id": "1782", "type": "ProteinMutation", "text": [ "His3543Tyr" ], "offsets": [ [ 908, 918 ] ], "normalized": [] }, { "id": "1783", "type": "ProteinMutation", "text": [ "H3543Y" ], "offsets": [ [ 945, 951 ] ], "normalized": [] }, { "id": "1784", "type": "ProteinMutation", "text": [ "H3543Y" ], "offsets": [ [ 990, 996 ] ], "normalized": [] }, { "id": "1785", "type": "ProteinMutation", "text": [ "Arg 3500 Gln" ], "offsets": [ [ 1063, 1075 ] ], "normalized": [] }, { "id": "1786", "type": "ProteinMutation", "text": [ "R3500Q" ], "offsets": [ [ 1077, 1083 ] ], "normalized": [] } ]

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[ { "id": "1793", "type": "title", "text": [ "POLG mutations associated with Alpers' syndrome and mitochondrial DNA depletion." ], "offsets": [ [ 0, 80 ] ] }, { "id": "1794", "type": "abstract", "text": [ "Alpers' syndrome is a fatal neurogenetic disorder first described more than 70 years ago. It is an autosomal recessive, developmental mitochondrial DNA depletion disorder characterized by deficiency in mitochondrial DNA polymerase gamma (POLG) catalytic activity, refractory seizures, neurodegeneration, and liver disease. In two unrelated pedigrees of Alpers' syndrome, each affected child was found to carry a homozygous mutation in exon 17 of the POLG locus that led to a Glu873Stop mutation just upstream of the polymerase domain of the protein. In addition, each affected child was heterozygous for the G1681A mutation in exon 7 that led to an Ala467Thr substitution in POLG, within the linker region of the protein." ], "offsets": [ [ 81, 802 ] ] } ]

[ { "id": "1790", "type": "ProteinMutation", "text": [ "Glu873Stop" ], "offsets": [ [ 556, 566 ] ], "normalized": [] }, { "id": "1791", "type": "DNAMutation", "text": [ "G1681A" ], "offsets": [ [ 689, 695 ] ], "normalized": [] }, { "id": "1792", "type": "ProteinMutation", "text": [ "Ala467Thr" ], "offsets": [ [ 730, 739 ] ], "normalized": [] } ]

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[ { "id": "1803", "type": "title", "text": [ "Identification of three F5 gene mutations associated with inherited coagulation factor V deficiency in two Chinese pedigrees." ], "offsets": [ [ 0, 125 ] ] }, { "id": "1804", "type": "abstract", "text": [ "To investigate the molecular defects in two Chinese pedigrees with inherited factor V (FV) deficiency. A 37-year-old male (proband 1) and an 18-month-old boy (proband 2) were diagnosed as inherited coagulation FV deficiency by severely reduced plasma levels of FV activity and antigen. All 25 exons and their flanking sequence of F5 gene were amplified by polymerase chain reaction (PCR) for both probands and the PCR products were directly sequenced. Total RNA was extracted from the peripheral lymphocytes of proband 1 for detecting the changes at mRNA level. The homozygous deletion IVS8 -2A>G was identified in the F5 gene of proband 1 and complementary DNA (cDNA) analysis revealed the abolishment of the canonical splicing site by the mutation and the activation of the cryptic acceptor site 24 bp upstream instead. The insertion introduced eight additional amino acids (AA) into the FV protein. Two heterozygous mutations of F5 gene were discovered in proband 2. The 2238-9del AG in exon 13 introduced a premature termination code at 689 AA and the substitution of G6410 by T in exon 23 lead to the missense mutation Gly2079Val. Three F5 gene mutations, IVS8 -2A>G, 2238-9del AG and G6410T, have been identified in two Chinese pedigree with congenital FV deficiency, respectively." ], "offsets": [ [ 126, 1413 ] ] } ]

[ { "id": "1796", "type": "DNAMutation", "text": [ "IVS8 -2A>G" ], "offsets": [ [ 712, 722 ] ], "normalized": [] }, { "id": "1797", "type": "DNAMutation", "text": [ "2238-9del AG" ], "offsets": [ [ 1100, 1112 ] ], "normalized": [] }, { "id": "1798", "type": "DNAMutation", "text": [ "G6410 by T" ], "offsets": [ [ 1198, 1208 ] ], "normalized": [] }, { "id": "1799", "type": "ProteinMutation", "text": [ "Gly2079Val" ], "offsets": [ [ 1250, 1260 ] ], "normalized": [] }, { "id": "1800", "type": "DNAMutation", "text": [ "IVS8 -2A>G" ], "offsets": [ [ 1287, 1297 ] ], "normalized": [] }, { "id": "1801", "type": "DNAMutation", "text": [ "2238-9del AG" ], "offsets": [ [ 1299, 1311 ] ], "normalized": [] }, { "id": "1802", "type": "DNAMutation", "text": [ "G6410T" ], "offsets": [ [ 1316, 1322 ] ], "normalized": [] } ]

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[ { "id": "1822", "type": "title", "text": [ "Four novel mutations in the thiazide-sensitive Na-Cl co-transporter gene in Japanese patients with Gitelman's syndrome." ], "offsets": [ [ 0, 119 ] ] }, { "id": "1823", "type": "abstract", "text": [ "BACKGROUND: Gitelman's syndrome (GS) is an autosomal recessive disorder resulting from inactivating mutations in the thiazide-sensitive Na-Cl co-transporter (NCCT) gene. To date, almost 90 mutations have been identified. It is possible that there is a population-specific distribution of mutations. In this study, we analysed mutations in the NCCT gene of seven Japanese patients with GS. METHODS: Peripheral blood mononuclear cells were isolated from patients with GS, their family members and healthy control subjects. A mutation analysis of the NCCT gene was performed completely by direct automated sequencing of polymerase chain reaction-amplified DNA products. In patients with a deletion or splice site mutation, we undertook cDNA sequence analysis. RESULTS: We identified nine mutations. Five of them [c.185C>T (Thr60Met), c.1712C>T (Ala569Val), c.1930C>T (Arg642Cys), c.2552T>A (Leu849His) and c.1932delC] have been reported in Japanese patients, but not in GS patients from other ethnic groups. The remaining four mutations [c.7A>T (Met1Leu), c.1181_1186+20del26, c.1811_1812delAT and IVS16+1G>A] were novel. In cDNA derived from a patient with c.1181_1186+20del26, a deletion of exon 9 and a frameshift at the start of exon 10 were observed. In cDNA derived from patients with IVS16+1G>A, an additional 96 bp insertion between exons 16 and 17 was observed. Six out of seven patients were compound heterozygotes, and the remaining one carried a single heterozygous mutation. CONCLUSIONS: We found four novel mutations in the NCCT gene in seven Japanese patients with GS. Moreover, our study suggests that the distribution of mutations in the NCCT gene in Japanese GS patients potentially differs from that in other populations." ], "offsets": [ [ 120, 1857 ] ] } ]

[ { "id": "1806", "type": "DNAMutation", "text": [ "c.185C>T" ], "offsets": [ [ 930, 938 ] ], "normalized": [] }, { "id": "1807", "type": "ProteinMutation", "text": [ "Thr60Met" ], "offsets": [ [ 940, 948 ] ], "normalized": [] }, { "id": "1808", "type": "DNAMutation", "text": [ "c.1712C>T" ], "offsets": [ [ 951, 960 ] ], "normalized": [] }, { "id": "1809", "type": "ProteinMutation", "text": [ "Ala569Val" ], "offsets": [ [ 962, 971 ] ], "normalized": [] }, { "id": "1810", "type": "DNAMutation", "text": [ "c.1930C>T" ], "offsets": [ [ 974, 983 ] ], "normalized": [] }, { "id": "1811", "type": "ProteinMutation", "text": [ "Arg642Cys" ], "offsets": [ [ 985, 994 ] ], "normalized": [] }, { "id": "1812", "type": "DNAMutation", "text": [ "c.2552T>A" ], "offsets": [ [ 997, 1006 ] ], "normalized": [] }, { "id": "1813", "type": "ProteinMutation", "text": [ "Leu849His" ], "offsets": [ [ 1008, 1017 ] ], "normalized": [] }, { "id": "1814", "type": "DNAMutation", "text": [ "c.1932delC" ], "offsets": [ [ 1023, 1033 ] ], "normalized": [] }, { "id": "1815", "type": "DNAMutation", "text": [ "c.7A>T" ], "offsets": [ [ 1155, 1161 ] ], "normalized": [] }, { "id": "1816", "type": "ProteinMutation", "text": [ "Met1Leu" ], "offsets": [ [ 1163, 1170 ] ], "normalized": [] }, { "id": "1817", "type": "DNAMutation", "text": [ "c.1181_1186+20del26" ], "offsets": [ [ 1173, 1192 ] ], "normalized": [] }, { "id": "1818", "type": "DNAMutation", "text": [ "c.1811_1812delAT" ], "offsets": [ [ 1194, 1210 ] ], "normalized": [] }, { "id": "1819", "type": "DNAMutation", "text": [ "IVS16+1G>A" ], "offsets": [ [ 1215, 1225 ] ], "normalized": [] }, { "id": "1820", "type": "DNAMutation", "text": [ "c.1181_1186+20del26" ], "offsets": [ [ 1275, 1294 ] ], "normalized": [] }, { "id": "1821", "type": "DNAMutation", "text": [ "IVS16+1G>A" ], "offsets": [ [ 1408, 1418 ] ], "normalized": [] } ]

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[ { "id": "1828", "type": "title", "text": [ "Compound heterozygous mutations in the SRD5A2 gene exon 4 in a male pseudohermaphrodite patient of Chinese origin." ], "offsets": [ [ 0, 114 ] ] }, { "id": "1829", "type": "abstract", "text": [ "The goal of this study was to perform 5-alpha-reductase type 2 gene (SRD5A2) analysis in a male pseudohermaphrodite (MPH) patient with normal testosterone (T) production and normal androgen receptor (AR) gene coding sequences. A patient of Chinese origin with ambiguous genitalia at 14 months, a 46,XY karyotype, and normal T secretion under human chorionic gonadotropin (hCG) stimulation underwent a gonadectomy at 20 months. Exons 1-8 of the AR gene and exons 1-5 of the SRD5A2 gene were sequenced from peripheral blood DNA. AR gene coding sequences were normal. SRD5A2 gene analysis revealed 2 consecutive mutations in exon 4, each located in a different allele: 1) a T nucleotide deletion, which predicts a frameshift mutation from codon 219, and 2) a missense mutation at codon 227, where the substitution of guanine (CGA) by adenine (CAA) predicts a glutamine replacement of arginine (R227Q). Testes located in the inguinal canal showed a normal morphology for age. The patient was a compound heterozygote for SRD5A2 mutations, carrying 2 mutations in exon 4. The patient showed an R227Q mutation that has been described in an Asian population and MPH patients, along with a novel frameshift mutation, Tdel219. Testis morphology showed that, during early infancy, the 5-alpha-reductase enzyme deficiency may not have affected interstitial or tubular development." ], "offsets": [ [ 115, 1483 ] ] } ]

[ { "id": "1825", "type": "ProteinMutation", "text": [ "R227Q" ], "offsets": [ [ 1006, 1011 ] ], "normalized": [] }, { "id": "1826", "type": "ProteinMutation", "text": [ "R227Q" ], "offsets": [ [ 1203, 1208 ] ], "normalized": [] }, { "id": "1827", "type": "DNAMutation", "text": [ "Tdel219" ], "offsets": [ [ 1323, 1330 ] ], "normalized": [] } ]

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[ { "id": "1831", "type": "title", "text": [ "Single-strand conformation polymorphism analysis of the FMR1 gene in autistic and mentally retarded children in Japan." ], "offsets": [ [ 0, 118 ] ] }, { "id": "1832", "type": "abstract", "text": [ "Fragile X syndrome is one of the most common causes of mental retardation in males, and patients with fragile X syndrome occasionally develop autism. It is usually caused by an expansion of the trinucleotide repeat in the 5'-untranslated region of the FMR1 gene, but in a small number of patients deletions and point mutations have been identified. We screened all 17 exons of the FMR1 gene for mutations in 90 autistic or mentally retarded children using polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis. No mutations were found in 76 male patients. However, one female patient was heterozygous for a normal allele and a mutant allele with an A to C substitution at nucleotide 879 in exon 9. This mutation was not found in 50 controls. Reverse transcription-PCR revealed that a large proportion of the mutant transcripts were spliced aberrantly, causing premature termination of the protein synthesis. Although uncommon, point mutations in the FMR1 gene may be a cause of autism and mental retardation in Japanese patients." ], "offsets": [ [ 119, 1182 ] ] } ]

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[ { "id": "1834", "type": "title", "text": [ "Expression mapping at 12p12-13 in advanced prostate carcinoma." ], "offsets": [ [ 0, 62 ] ] }, { "id": "1835", "type": "abstract", "text": [ "We have previously mapped a putative prostate cancer tumor-suppressor gene to a 1-2 Mb region of 12p12-13. Initial work to identify the tumor suppressor at this locus focused on candidates previously implicated in malignancy; however, mutational and methylation analyses failed to identify significant genomic events. An alternative approach is to use expression analysis to prioritize the genes within the region of interest. This experimental design is based on the hypothesis that tumor-suppressor genes demonstrate decreased expression in tumors compared to normals. Herein, we narrow the region of interest using deletion mapping data and employ expression analysis to prioritize the genes in the minimal deleted region. Highly informative polymorphic markers spanning our region were used to assess for loss of heterozygosity in 99 tumor and normal DNA pairs. The minimal region of deletion was determined to be approximately 500 kb bounded by D12S391 and A002Q26. Publically available databases place 7 genes within this minimal deletion region. An additional 3 genes lie just outside this minimal deletion region and could possibly be inactivated by deletion of promoter, 3'-untranslated region sequences or alternative splice variants. Relative levels of expression of these 10 candidate genes were determined in 6 normal prostates, 5 local prostate tumors, 9 prostate lymph node metastases, 6 prostate cancer cell lines and 12 prostate cancer xenografts using quantitative RT-PCR. DUSP16, FLJ10298 and BCLG were significantly downregulated in both clinical tumors and cultured prostate cancer tissue, indicating that one or all may be critical to initiation or progression of prostate carcinoma." ], "offsets": [ [ 63, 1768 ] ] } ]

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[ { "id": "1841", "type": "title", "text": [ "The Arg753GLn polymorphism of the human toll-like receptor 2 gene in tuberculosis disease." ], "offsets": [ [ 0, 90 ] ] }, { "id": "1842", "type": "abstract", "text": [ "Toll-like receptor 2 (TLR2), a member of the Toll-like receptor family, plays an important role in recognition of, and subsequent immune response activation against, mycobacteria. The genetic polymorphism of TLR2 (arginine to glutamine substitution at residue 753 (Arg753Gln)) has been associated with a negative influence on TLR2 function, which may, in turn, determine the innate host response to mycobacteria. The aim of the present study was to investigate the Arg753Gln single nucleotide polymorphism of the TLR2 gene in tuberculosis (TB) patients compared to healthy controls. A retrospective case/control study was carried out. The Arg753Gln polymorphism of the TLR2 gene was studied in 151 TB patients compared to 116 ethnically and age-matched healthy control subjects. The TLR2 polymorphism (adenine (A) allele) was observed in 17.9 and 7.7% of TB patients and controls, respectively. When the ratios of the three genotypes were compared between the two groups, the AA genotype was found to be more significantly associated with TB. Allele frequencies for guanine (G) and A were found to be 0.95 and 0.05 in the control group and 0.86 and 0.14 in the TB patient group, respectively. The risk of developing TB disease was increased 6.04- and 1.60-fold for carriers of the AA and GA genotypes, respectively. In conclusion, the present data suggest that the arginine to glutamine substitution at residue 753 polymorphism of the Toll-like receptor 2 gene influences the risk of developing tuberculosis." ], "offsets": [ [ 91, 1599 ] ] } ]

[ { "id": "1837", "type": "ProteinMutation", "text": [ "Arg753GLn" ], "offsets": [ [ 4, 13 ] ], "normalized": [] }, { "id": "1838", "type": "ProteinMutation", "text": [ "Arg753Gln" ], "offsets": [ [ 356, 365 ] ], "normalized": [] }, { "id": "1839", "type": "ProteinMutation", "text": [ "Arg753Gln" ], "offsets": [ [ 556, 565 ] ], "normalized": [] }, { "id": "1840", "type": "ProteinMutation", "text": [ "Arg753Gln" ], "offsets": [ [ 730, 739 ] ], "normalized": [] } ]

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[ { "id": "1844", "type": "title", "text": [ "Homozygous deletions within the 11q13 cervical cancer tumor-suppressor locus in radiation-induced, neoplastically transformed human hybrid cells." ], "offsets": [ [ 0, 145 ] ] }, { "id": "1845", "type": "abstract", "text": [ "Studies on nontumorigenic and tumorigenic human cell hybrids derived from the fusion of HeLa (a cervical cancer cell line) with GM00077 (a normal skin fibroblast cell line) have demonstrated \"functional\" tumor-suppressor activity on chromosome 11. It has been shown that several of the neoplastically transformed radiation-induced hybrid cells called GIMs (gamma ray induced mutants), isolated from the nontumorigenic CGL1 cells, have lost one copy of the fibroblast chromosome 11. We hypothesized, therefore, that the remaining copy of the gene might be mutated in the cytogenetically intact copy of fibroblast chromosome 11. Because a cervical cancer tumor suppressor locus has been localized to chromosome band 11q13, we performed deletion-mapping analysis of eight different GIMs using a total of 32 different polymorphic and microsatellite markers on the long arm (q arm) of chromosome 11. Four irradiated, nontumorigenic hybrid cell lines, called CONs, were also analyzed. Allelic deletion was ascertained by the loss of a fibroblast allele in the hybrid cell lines. The analysis confirmed the loss of a fibroblast chromosome 11 in five of the GIMs. Further, homozygous deletion (complete loss) of chromosome band 11q13 band sequences, including that of D11S913, was observed in two of the GIMs. Detailed mapping with genomic sequences localized the homozygous deletion to a 5.7-kb interval between EST AW167735 and EST F05086. Southern blot hybridization using genomic DNA probes from the D11S913 locus confirmed the existence of homozygous deletion in the two GIM cell lines. Additionally, PCR analysis showed a reduction in signal intensity for a marker mapped 31 kb centromeric of D11S913 in four other GIMs. Finally, Northern blot hybridization with the genomic probes revealed the presence of a novel >15-kb transcript in six of the GIMs. These transcripts were not observed in the nontumorigenic hybrid cell lines. Because the chromosome 11q13 band deletions in the tumorigenic hybrid cell lines overlapped with the minimal deletion in cervical cancer, the data suggest that the same gene may be involved in the development of cervical cancer and in radiation-induced carcinogenesis. We propose that a gene localized in proximity to the homozygous deletion is the candidate tumor-suppressor gene." ], "offsets": [ [ 146, 2455 ] ] } ]

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[ { "id": "1859", "type": "title", "text": [ "Structural and biochemical basis for novel mutations in homozygous Israeli maple syrup urine disease patients: a proposed mechanism for the thiamin-responsive phenotype." ], "offsets": [ [ 0, 169 ] ] }, { "id": "1860", "type": "abstract", "text": [ "Maple syrup urine disease (MSUD) results from mutations affecting different subunits of the mitochondrial branched-chain alpha-ketoacid dehydrogenase complex. In this study, we identified seven novel mutations in MSUD patients from Israel. These include C219W-alpha (TGC to TGG) in the E1alpha subunit; H156Y-beta (CAT to TAT), V69G-beta (GTT to GGT), IVS 9 del[-7:-4], and 1109 ins 8bp (exon 10) in the E1beta subunit; and H391R (CAC to CGC) and S133stop (TCA to TGA) affecting the E2 subunit of the branched-chain alpha-ketoacid dehydrogenase complex. Recombinant E1 proteins carrying the C219W-alpha or H156Y-beta mutation show no catalytic activity with defective subunit assembly and reduced binding affinity for cofactor thiamin diphosphate. The mutant E1 harboring the V69G-beta substitution cannot be expressed, suggesting aberrant folding caused by this mutation. These E1 mutations are ubiquitously associated with the classic phenotype in homozygous-affected patients. The H391R substitution in the E2 subunit abolishes the key catalytic residue that functions as a general base in the acyltransfer reaction, resulting in a completely inactive E2 component. However, wild-type E1 activity is enhanced by E1 binding to this full-length mutant E2 in vitro. We propose that the augmented E1 activity is responsible for robust thiamin responsiveness in homozygous patients carrying the H391R E2 mutation and that the presence of a full-length mutant E2 is diagnostic of this MSUD phenotype. The present results offer a structural and biochemical basis for these novel mutations and will facilitate DNA-based diagnosis for MSUD in the Israeli population." ], "offsets": [ [ 170, 1830 ] ] } ]

[ { "id": "1847", "type": "ProteinMutation", "text": [ "C219W" ], "offsets": [ [ 424, 429 ] ], "normalized": [] }, { "id": "1848", "type": "ProteinMutation", "text": [ "H156Y" ], "offsets": [ [ 473, 478 ] ], "normalized": [] }, { "id": "1849", "type": "ProteinMutation", "text": [ "V69G" ], "offsets": [ [ 498, 502 ] ], "normalized": [] }, { "id": "1850", "type": "DNAMutation", "text": [ "IVS 9 del[-7:-4]" ], "offsets": [ [ 522, 538 ] ], "normalized": [] }, { "id": "1851", "type": "DNAMutation", "text": [ "1109 ins 8bp" ], "offsets": [ [ 544, 556 ] ], "normalized": [] }, { "id": "1852", "type": "ProteinMutation", "text": [ "H391R" ], "offsets": [ [ 594, 599 ] ], "normalized": [] }, { "id": "1853", "type": "ProteinMutation", "text": [ "S133stop" ], "offsets": [ [ 617, 625 ] ], "normalized": [] }, { "id": "1854", "type": "ProteinMutation", "text": [ "C219W" ], "offsets": [ [ 761, 766 ] ], "normalized": [] }, { "id": "1855", "type": "ProteinMutation", "text": [ "H156Y" ], "offsets": [ [ 776, 781 ] ], "normalized": [] }, { "id": "1856", "type": "ProteinMutation", "text": [ "V69G" ], "offsets": [ [ 946, 950 ] ], "normalized": [] }, { "id": "1857", "type": "ProteinMutation", "text": [ "H391R" ], "offsets": [ [ 1154, 1159 ] ], "normalized": [] }, { "id": "1858", "type": "ProteinMutation", "text": [ "H391R" ], "offsets": [ [ 1563, 1568 ] ], "normalized": [] } ]

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[ { "id": "1867", "type": "title", "text": [ "Haplotypes and DNA sequence variation within and surrounding the transthyretin gene: genotype-phenotype correlations in familial amyloid polyneuropathy (V30M) in Portugal and Sweden." ], "offsets": [ [ 0, 182 ] ] }, { "id": "1868", "type": "abstract", "text": [ "Familial amyloid polyneuropathy (FAP) is a lethal autosomal dominant disorder in which fibrils derived from mutant forms of transthyretin (TTR), the normal plasma carrier of thyroxine (T(4)) and retinol-binding protein, are deposited in tissues. Over 80 TTR sequence variants are associated with FAP, but the amino-acid substitutions alone do not completely explain the variability in disease penetrance, pathology and clinical course. To analyze the factors possibly contributing to this phenotypic variability, we characterized the variations within the wild-type and mutant (Val30Met) TTR genes and their flanking sequences by performing extended microsatellite haplotype analyses, sequencing and single-nucleotide polymorphism haplotyping of genomic DNA from Portuguese and Swedish carriers of V30M. We identified 10 new polymorphisms in the TTR untranslated regions, eight resulting from single-base substitutions and two arising from insertion/deletions in dinucleotide repeat sequences. The data suggest that the onset of symptoms of FAP V30M may be modulated by an interval downstream of TTR on the accompanying noncarrier chromosome (defined by microsatellites D18S457 and D18S456), but not by the immediately 5'- and 3'-flanking sequences of TTR. During the course of these studies, we also encountered the first instance in which the previously described intragenic haplotype III may be associated with V30M FAP in the Portuguese population." ], "offsets": [ [ 183, 1635 ] ] } ]

[ { "id": "1862", "type": "ProteinMutation", "text": [ "V30M" ], "offsets": [ [ 153, 157 ] ], "normalized": [] }, { "id": "1863", "type": "ProteinMutation", "text": [ "Val30Met" ], "offsets": [ [ 761, 769 ] ], "normalized": [] }, { "id": "1864", "type": "ProteinMutation", "text": [ "V30M" ], "offsets": [ [ 981, 985 ] ], "normalized": [] }, { "id": "1865", "type": "ProteinMutation", "text": [ "V30M" ], "offsets": [ [ 1228, 1232 ] ], "normalized": [] }, { "id": "1866", "type": "ProteinMutation", "text": [ "V30M" ], "offsets": [ [ 1597, 1601 ] ], "normalized": [] } ]

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[ { "id": "1870", "type": "title", "text": [ "Germline deletions of EXO1 do not cause colorectal tumors and lesions which are null for EXO1 do not have microsatellite instability." ], "offsets": [ [ 0, 133 ] ] }, { "id": "1871", "type": "abstract", "text": [ "Exonuclease 1 (EXO1) is a candidate gene for colorectal tumor susceptibility because it is believed to play a role in mismatch repair. There have been several studies investigating the role of EXO1 in mismatch repair but few investigating its role in causing clinical disease. In one recent study, germline variants of EXO1 were reported to be associated with predisposition to colorectal cancer in families with phenotypes similar to hereditary nonpolyposis colon cancer (HNPCC). We recently identified nine individuals from two British families with multiple cutaneous and uterine leiomyomatosis with independently arising heterozygous germline deletions of 1q42.3 approximately q43 encompassing not only FH, the multiple leiomyomatosis-associated gene, but also several flanking genes, including EXO1. We investigated these families for any indication of predisposition to colorectal cancer or other HNPCC spectrum cancers by means of detailed questionnaires, interviews, and examination of EXO1-null skin leiomyomata for microsatellite instability (MSI). No individual in these families had developed colorectal cancer or known colorectal adenomas, and none had any symptoms warranting gastrointestinal or other investigation. EXO1-null tumors showed no evidence of MSI. This study questions the functional significance of previously reported variants of EXO1 reported in HNPCC-like families and suggests that in humans there may be other as yet undiscovered proteins that have exonuclease function overlapping with that of EXO1 in DNA mismatch repair. Also of interest is the absence of phenotypic abnormality apart from multiple leiomyomatosis in any deletion carrier even though the adjacent genes RGS7, KMO, CHML, and OPN3 were also deleted." ], "offsets": [ [ 134, 1883 ] ] } ]

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[ { "id": "1874", "type": "title", "text": [ "Beta-thalassemia in association with a new delta-chain hemoglobin variant [delta116(g18)Arg-->Leu]: implications for carrier screening and prenatal diagnosis." ], "offsets": [ [ 0, 158 ] ] }, { "id": "1875", "type": "abstract", "text": [ "We describe a complicated genetic counseling and prenatal diagnostic case involving an East Indian couple that had lost two consecutive pregnancies. Hemoglobinopathy screening was conducted to investigate the possibility of Hb Bart's hydrops fetalis or Hb H hydrops fetalis. The initial work-up indicated that alpha-thalassemia was not a contributing factor, with both parents being carriers of single gene deletions (-alpha(3.7)/alphaalpha). However, the Hb electrophoresis results indicated that the couple might be at risk for having children with Hb E/Hb Lepore disease. Subsequent DNA testing demonstrated that the father carried the Hb E mutation, but failed to confirm that the mother carries the Hb Lepore deletion. Sequence analysis revealed that the mother was heterozygous for a common East Indian beta(0)-thalassemia mutation, yet had a normal level of Hb A(2). The mother also carried a previously unreported missense mutation of the delta-globin gene, in cis with the beta(0)-thalassemia mutation, which gave rise to the minor Hb variant originally misidentified as Hb Lepore. This case illustrates the importance of comprehensive molecular analyses for accurate assessment of genetic risks for hemoglobinopathy syndromes." ], "offsets": [ [ 159, 1395 ] ] } ]

[ { "id": "1873", "type": "ProteinMutation", "text": [ "Arg-->Leu" ], "offsets": [ [ 88, 97 ] ], "normalized": [] } ]

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[ { "id": "1883", "type": "title", "text": [ "Novel polypyrimidine variation (IVS46: del T -39...-46) in ABCA1 causes exon skipping and contributes to HDL cholesterol deficiency in a family with premature coronary disease." ], "offsets": [ [ 0, 176 ] ] }, { "id": "1884", "type": "abstract", "text": [ "Recent studies have implicated mutations in the ATP-binding cassette transporter A1, ABCA1, as a cause of Tangier disease (TD) and familial hypoalphalipoproteinemia (FHA). We investigated a proband with very low levels of high-density lipoprotein cholesterol (HDL-C, 6 mg/dL) and a history of premature coronary heart disease (CHD). Sequencing of the ABCA1 gene revealed 2 distinct variants. The first mutation was a G5947A substitution (R1851Q). The second mutation was a single-nucleotide deletion of thymidine in a polypyrimidine tract located 33 to 46 bps upstream to the start of exon 47. This mutation does not involve the 3' acceptor splice site and is outside the lariat branchpoint sequence (IVS46: del T -39...-46). Amplification of cDNA obtained in cultured fibroblasts of the proband and affected family member revealed an abnormally spliced cDNA sequence with skipping of exon 47. These variants were not identified in over 400 chromosomes of healthy whites. Compound heterozygotes (n=4) exhibited the lowest HDL-C (11+/-5 mg/dL) and ApoA-I (35+/-15 mg/dL) compared with wild-type (n=25) (HDL-C 51+/-14 mg/dL; ApoA-I 133+/-21 mg/dL) (P<0.0005) or subjects affected with either R1851Q (n=6) (HDL-C 36+/-8; ApoA-I 117+/-19) or IVS46: del T -39...-46 (n=5) (HDL-C 31+9; ApoA-I 115+28 (P<0.01). These data suggest that polypyrimidine tract variation may represent a novel mechanism for altered splicing and exon skipping that is independent of traditional intronic variants as previously identified in acceptor/donor splice regions or the lariat branchpoint domain." ], "offsets": [ [ 177, 1751 ] ] } ]

[ { "id": "1877", "type": "DNAMutation", "text": [ "IVS46: del T -39...-46" ], "offsets": [ [ 32, 54 ] ], "normalized": [] }, { "id": "1878", "type": "DNAMutation", "text": [ "G5947A" ], "offsets": [ [ 594, 600 ] ], "normalized": [] }, { "id": "1879", "type": "ProteinMutation", "text": [ "R1851Q" ], "offsets": [ [ 615, 621 ] ], "normalized": [] }, { "id": "1880", "type": "DNAMutation", "text": [ "IVS46: del T -39...-46" ], "offsets": [ [ 878, 900 ] ], "normalized": [] }, { "id": "1881", "type": "ProteinMutation", "text": [ "R1851Q" ], "offsets": [ [ 1367, 1373 ] ], "normalized": [] }, { "id": "1882", "type": "DNAMutation", "text": [ "IVS46: del T -39...-46" ], "offsets": [ [ 1415, 1437 ] ], "normalized": [] } ]

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[ { "id": "1886", "type": "title", "text": [ "Frequency of polymorphisms of genes coding for HIV-1 co-receptors CCR5 and CCR2 in a Brazilian population." ], "offsets": [ [ 0, 106 ] ] }, { "id": "1887", "type": "abstract", "text": [ "Entry of human immunodeficiency type 1 virus (HIV-1) into target cells requires both CD(4)and one of the chemokine receptors. Viruses predominantly use one, or occasionally both, of the major co-receptors CCR5 and CXCR4, although other receptors, including CCR2B and CCR3, function as minor co-receptors. A 32-nucleotide deletion (D32) within the b-chemokine receptor 5 gene (CCR5) has been described in subjects who remain uninfected despite extensive exposition to HIV-1. The heterozygous genotype delays disease progression. This allele is common among Caucasians, but has not been found in people of African or Asian ancestry. A more common transition involving a valine to isoleucine switch in transmembrane domain I of CCR2B (64I), with unknown functional consequences, was found to delay disease progression but not to reduce infection risk. As the Brazilian population consists of a mixture of several ethnic groups, we decided to examine the genotype frequency of these polymorphisms in this country. There were 11.5% CCR5 heterozygotes among the HIV-1 infected population and 12.5% among uninfected individuals, similar to data from North America and Western Europe. The prevalence of CCR2-64I homozygotes and heterozygotes was 0.06 and 15.2%, respectively, also similar to what is known for North America and Western Europe." ], "offsets": [ [ 107, 1442 ] ] } ]

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[ { "id": "1892", "type": "title", "text": [ "Progressive decline of vasopressin secretion in familial autosomal dominant neurohypophyseal diabetes insipidus presenting a novel mutation in the vasopressin-neurophysin II gene." ], "offsets": [ [ 0, 179 ] ] }, { "id": "1893", "type": "abstract", "text": [ "OBJECTIVE: Familial autosomal dominant neurohypophyseal diabetes insipidus (FNDI) is a rare form of central diabetes insipidus (DI), which is caused by mutations in the vasopressin-neurophysin II (AVP-NPII) gene. The present study evaluated the AVP secretion over time and analysed the structure of the AVP-NPII gene in a Brazilian family with FNDI. SUBJECTS AND DESIGN: Four affected members and one nonaffected member from one Brazilian family with FNDI were studied. The diagnosis of central DI was established by fluid deprivation test and hypertonic saline infusion. Two affected members were assessed twice within a 6-year interval. For molecular analysis, genomic DNA was extracted and the AVP-NPII gene was amplified by polymerase chain reaction. RESULTS: The functional assessment of patients with FNDI over time confirmed a progressive loss in AVP secretion. Two patients were first diagnosed as partial central DI and, several years later, they developed severe central DI. Sequencing analysis revealed a heterozygous new point mutation in the nucleotide 1892 in the coding sequence for neurophysin-II of the AVP-NPII gene (1892G>C) predicting an amino acid substitution (A68P) in all affected members. CONCLUSION: Our data demonstrate a gradual vasopressinergic deficiency due to a novel mutation in the AVP-NPII gene in a Brazilian family with FNDI. The accumulation of A68P mutated precursor might have a cytotoxicity effect, leading to a gradual death of magnocellular neurones, and a progressive decline in AVP secretion." ], "offsets": [ [ 180, 1717 ] ] } ]

[ { "id": "1889", "type": "DNAMutation", "text": [ "1892G>C" ], "offsets": [ [ 1315, 1322 ] ], "normalized": [] }, { "id": "1890", "type": "ProteinMutation", "text": [ "A68P" ], "offsets": [ [ 1363, 1367 ] ], "normalized": [] }, { "id": "1891", "type": "ProteinMutation", "text": [ "A68P" ], "offsets": [ [ 1563, 1567 ] ], "normalized": [] } ]

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[ { "id": "1896", "type": "title", "text": [ "Congenital hypothyroidism due to a new deletion in the sodium/iodide symporter protein." ], "offsets": [ [ 0, 87 ] ] }, { "id": "1897", "type": "abstract", "text": [ "OBJECTIVE: Iodide transport defect (ITD) is a rare disorder characterised by an inability of the thyroid to maintain an iodide gradient across the basolateral membrane of thyroid follicular cells, that often results in congenital hypothyroidism. When present the defect is also found in the salivary glands and gastric mucosa and it has been shown to arise from abnormalities of the sodium/iodide symporter (NIS). PATIENT: We describe a woman with hypothyroidism identified at the 3rd month of life. The diagnosis of ITD was suspected because of nodular goitre, and little if any iodide uptake by the thyroid and salivary glands. Treatment with iodide partially corrected the hypothyroidism; however, long-term substitution therapy with L-thyroxine was started. MEASUREMENTS: Thyroid radioiodide uptake was only 1.4% and 0.3% at 1 and 24 h after the administration of recombinant human TSH. The saliva to plasma I- ratio was 1.1 indicating that the inability of the thyroid gland to concentrate I- was also present in the salivary glands. RESULTS: Analysis of the patient's NIS gene revealed a 15 nucleotide (nt) deletion of the coding sequence (nt 1314 through nt 1328) and the insertion of 15 nt duplicating the first 15 nt of the adjacent intron. The patient was homozygous for this insertion/deletion, while both consanguineous parents were heterozygous. This deletion predicts the production of a protein lacking the five terminal amino acids of exon XI (439-443) which are located in the 6th intracellular loop. COS-7 cells transfected with a vector expressing the mutant del-(439-443) NIS failed to concentrate iodide, suggesting that the mutation was the direct cause of the ITD in this patient. CONCLUSION: In conclusion we describe the first Italian case of congenital hypothyroidism due to a new deletion in the NIS gene." ], "offsets": [ [ 88, 1920 ] ] } ]

[ { "id": "1895", "type": "DNAMutation", "text": [ "del-(439-443)" ], "offsets": [ [ 1666, 1679 ] ], "normalized": [] } ]

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[ { "id": "1899", "type": "title", "text": [ "Cdx-2 polymorphism in the promoter region of the human vitamin D receptor gene determines susceptibility to fracture in the elderly." ], "offsets": [ [ 0, 132 ] ] }, { "id": "1900", "type": "abstract", "text": [ "A Cdx-2 binding site polymorphism (G to A) in the promoter region of the human vitamin D receptor gene was reported. In an ecological study in eight ethnic groups and an association study in 2848 elderly whites, we found the A-allele to be associated with decreased fracture risk. Our findings expand previous similar findings in a Japanese study to whites and show a relationship with fracture risk of this functional polymorphism. INTRODUCTION: A single nucleotide polymorphism (SNP) within a binding site of the intestinal-specific transcription factor Cdx-2 in the promoter region of the human vitamin D receptor (VDR) gene was previously reported. It was found to modulate the transcription of the hVDR gene and to be associated with decreased bone mineral density in a small group of postmenopausal Japanese women. In this study, we investigated the relationship between the VDR Cdx-2 genotype and risk of fracture. METHODS: We first determined the location of this SNP in the VDR gene by sequencing analysis, and we developed an allele-specific multiplex polymerase chain reaction test to determine the Cdx-2 genotype. We then performed an ecological study in eight ethnic groups and an association analysis in a large epidemiological cohort of 2848 Dutch white men and women, > or = 55 years old. RESULTS AND CONCLUSIONS: The location of the G to A substitution was found in the promoter region of exon le (le-G-1739A) of the VDR gene. By comparing the frequency of the A-allele in eight different ethnic groups, we observed a negative correlation between prevalence of the A-allele and published hip fracture incidence rates in these ethnic groups (p = 0.006 for men and p = 0.02 for women), suggesting a protective effect of this allele on fracture risk. Subsequently, in the association study, the A-allele (population frequency 19%) was observed to have a protective effect on occurrence of osteoporotic fractures, especially for nonvertebral fracture in women (relative risk of AA versus GG genotype is 0.2; 95% CI, 0.05-0.8). This effect remained after adjustment for age, weight, and bone mineral density. We conclude that the A-allele of the VDR Cdx-2 polymorphism is present in whites, albeit at low frequency, and show a protective effect of this allele on risk of fracture." ], "offsets": [ [ 133, 2425 ] ] } ]

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[ { "id": "1902", "type": "title", "text": [ "A glycine to aspartic acid substitution of COL2A1 in a family with the Strudwick variant of spondyloepimetaphyseal dysplasia." ], "offsets": [ [ 0, 125 ] ] }, { "id": "1903", "type": "abstract", "text": [ "BACKGROUND: Spondyloepimetaphyseal dysplasia (SEMD) is one of a clinically heterogeneous group of skeletal disorders, characterized by defective growth and modelling of the spine and long bones. Common clinical features include disproportionate short stature, malformed vertebrae and abnormal epiphyses or metaphyses. Some cases have been associated with mutations in the COL2A1 gene. AIM: To determine whether the autosomal dominant Strudwick-type SEMD in a three-generation family, showing specific phenotypical features such as chest deformity, limb shortening, myopia and early-onset degenerative osteoarthrosis, might be caused by a novel COL2A1 mutation. DESIGN: Genetic testing and clinical examination of family members. METHODS: Direct sequencing of PCR-amplified genomic DNA from the COL2A1 gene. RESULTS: A point mutation within exon 20 of the COL2A1 gene was identified that substituted a glycine for an aspartic acid residue at codon 262. DISCUSSION: All previously reported autosomal dominant mutations causing SEMD have substituted an obligate glycine within the triple helix, in particular at codons 292, 304 and 709 in the three reported Strudwick-type patients. Additionally, a recurrent glycine substitution at codon 154 has been identified in two unrelated Finnish cases with radiological features consistent with the Strudwick subtype. Our sixth helical glycine substitution extends the mutational spectrum and genotype/phenotype correlations of Strudwick-type SEMD." ], "offsets": [ [ 126, 1613 ] ] } ]

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[ { "id": "1908", "type": "title", "text": [ "Genetic polymorphisms of renin-angiotensin system and progression of interstitial nephritis." ], "offsets": [ [ 0, 92 ] ] }, { "id": "1909", "type": "abstract", "text": [ "Genes of the renin-angiotensin system (RAS) are involved in the progression of renal failure. Among them, the angiotensin-converting enzyme (ACE), angiotensinogen (AGT) and angiotensin II type 1 receptor (AT1R) genes are of particular interest. We examined polymorphisms of these three genes for association with the development of interstitial nephritis and progression to end-stage renal failure. The allele frequency and genotype distribution were compared in 90 patients with interstitial nephritis and 200 healthy controls. DNA samples were genotyped by polymerase chain reaction (PCR). We did not find statistically significant differences between groups in the insertion/deletion polymorphism of the ACE gene. An involvement of M235T polymorphism of the AGT gene in renal disease was observed in our study. The frequency of the T allele was higher in patients than in controls (32% vs. 24%). In the A1166C AT1R polymorphism the homozygous CC genotype was also more frequent in interstitial nephritis patients (7% vs. 3.5%). In patients carrying the C allele, an average time to ESRD was significantly shorter than in subjects with the AA genotype. Our study shows the association of the AGT and AT1R gene polymorphisms with the development and progression of interstitial nephritis. The C allele of the A1166C polymorphism appears to be a risk factor for faster disease progression." ], "offsets": [ [ 93, 1482 ] ] } ]

[ { "id": "1905", "type": "ProteinMutation", "text": [ "M235T" ], "offsets": [ [ 828, 833 ] ], "normalized": [] }, { "id": "1906", "type": "DNAMutation", "text": [ "A1166C" ], "offsets": [ [ 999, 1005 ] ], "normalized": [] }, { "id": "1907", "type": "DNAMutation", "text": [ "A1166C" ], "offsets": [ [ 1403, 1409 ] ], "normalized": [] } ]

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[ { "id": "1911", "type": "title", "text": [ "Epidemiology of tuberculosis on Gran Canaria: a 4 year population study using traditional and molecular approaches." ], "offsets": [ [ 0, 115 ] ] }, { "id": "1912", "type": "abstract", "text": [ "BACKGROUND: In recent years several population based studies using restriction fragment length polymorphism (RFLP) analysis have shown a higher rate of recent transmission of tuberculosis than previously thought. This study was undertaken to determine the transmission patterns of tuberculosis and the potential causes of recent transmission on the island of Gran Canaria (Spain). METHODS: The strains of all patients diagnosed with tuberculosis confirmed by culture between 1 January 1993 and 31 December 1996 were typed by RFLP using the insertion sequence IS6110. A cluster was defined as two or more isolates with an identical RFLP pattern. Epidemiological linkage through contact tracing was investigated. RESULTS: Of the total of 719 patients, 153 (21.3%) were excluded because there was inadequate bacterial DNA for genotyping (n=129) or the isolates of Mycobacterium tuberculosis had less than five copies of IS6110 (n=24). The isolates from 409 patients (72.3%) were grouped into 78 different clusters with an estimated 58.5% of the cases being due to recent transmission. Young age was the only significant predictor of clustering. Only in 147 (35.9%) of the 409 patients belonging to a cluster could an epidemiological link be found. 111 patients (19.6%) were identified as having had previous contact with a tuberculosis patient and 81 of them (72.9%) belonged to a cluster. The three largest clusters included 75, 49 and 20 patients, respectively. CONCLUSION: Recent transmission is frequent among patients with tuberculosis on Gran Canaria and could be associated with certain aspects of control measures. Some of the clusters described in the study could be due to the prevalence of particular strains of M tuberculosis on the island." ], "offsets": [ [ 116, 1865 ] ] } ]

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[ { "id": "1921", "type": "title", "text": [ "Spectrum of mutations in the arylsulfatase A gene in a Canadian DNA collection including two novel frameshift mutations, a new missense mutation (C488R) and an MLD mutation (R84Q) in cis with a pseudodeficiency allele." ], "offsets": [ [ 0, 218 ] ] }, { "id": "1922", "type": "abstract", "text": [ "We describe three novel mutations in the human arylsulfatase A gene in three patients with MLD, an autosomal recessive lysosomal storage disorder. An insertion, 2590_2591insCCCC in exon 8 and a deletion, 752_758delGCCGGCC, in exon 3 will both result in frameshifts. A mutation in exon 8, 2566T-->C, results in a missense mutation C488R, disrupting an unusual cysteine-knot at the C-terminal end of the protein. All three mutations are heterozygous with previously documented mutations. A previously reported mutation, R84Q was identified on a pseudodeficiency allele. These mutations are part of a heterogeneous spectrum of mutations found in a collection of DNA samples from MLD patients from across Canada and the USA." ], "offsets": [ [ 219, 939 ] ] } ]

[ { "id": "1914", "type": "ProteinMutation", "text": [ "C488R" ], "offsets": [ [ 146, 151 ] ], "normalized": [] }, { "id": "1915", "type": "ProteinMutation", "text": [ "R84Q" ], "offsets": [ [ 174, 178 ] ], "normalized": [] }, { "id": "1916", "type": "DNAMutation", "text": [ "2590_2591insCCCC" ], "offsets": [ [ 380, 396 ] ], "normalized": [] }, { "id": "1917", "type": "DNAMutation", "text": [ "752_758delGCCGGCC" ], "offsets": [ [ 423, 440 ] ], "normalized": [] }, { "id": "1918", "type": "DNAMutation", "text": [ "2566T-->C" ], "offsets": [ [ 507, 516 ] ], "normalized": [] }, { "id": "1919", "type": "ProteinMutation", "text": [ "C488R" ], "offsets": [ [ 549, 554 ] ], "normalized": [] }, { "id": "1920", "type": "ProteinMutation", "text": [ "R84Q" ], "offsets": [ [ 737, 741 ] ], "normalized": [] } ]

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[ { "id": "1928", "type": "title", "text": [ "The molecular basis for the thalassaemias in Sri Lanka." ], "offsets": [ [ 0, 55 ] ] }, { "id": "1929", "type": "abstract", "text": [ "The beta-globin gene mutations and the alpha-globin genes of 620 patients with the phenotype of severe to moderate thalassaemia from seven centres in Sri Lanka were analysed. Twenty-four beta-globin gene mutations were identified, three accounting for 84.5% of the 1240 alleles studied: IVSI-5 (G-->C) 56.2%; IVSI-1 (G-->A) 15.2%; and haemoglobin E (codon (CD)26 GAG-->GAA) 13.1%. Three new mutations were found; a 13-bp deletion removing the last nucleotide in CD6 to CD10 inclusively, IVSI-129 (A-->C) in the consensus splice site, and a frame shift, CD55 (-A). The allele frequency of alpha+ thalassaemia was 6.5% and 1.1% for -alpha3.7 and -alpha4.2 deletions respectively. Non-deletion alpha-thalassaemia was not observed. Triplicate or quadruplicate alpha-globin genes were unusually common. In 1.5% of cases it was impossible to identify beta-thalassaemia alleles, but in Kurunegala detailed family studies led to an explanation for the severe thalassaemia phenotype in every case, including a previously unreported instance of homozygosity for a quadruplicated alpha-globin gene together with beta-thalassaemia trait. These findings have implications for the control of thalassaemia in high-frequency populations with complex ethnic histories." ], "offsets": [ [ 56, 1307 ] ] } ]

[ { "id": "1924", "type": "DNAMutation", "text": [ "IVSI-5 (G-->C)" ], "offsets": [ [ 343, 357 ] ], "normalized": [] }, { "id": "1925", "type": "DNAMutation", "text": [ "IVSI-1 (G-->A)" ], "offsets": [ [ 365, 379 ] ], "normalized": [] }, { "id": "1926", "type": "DNAMutation", "text": [ "codon (CD)26 GAG-->GAA" ], "offsets": [ [ 406, 428 ] ], "normalized": [] }, { "id": "1927", "type": "DNAMutation", "text": [ "IVSI-129 (A-->C)" ], "offsets": [ [ 543, 559 ] ], "normalized": [] } ]

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[ { "id": "1932", "type": "title", "text": [ "Pacemaker channel dysfunction in a patient with sinus node disease." ], "offsets": [ [ 0, 67 ] ] }, { "id": "1933", "type": "abstract", "text": [ "The cardiac pacemaker current I(f) is a major determinant of diastolic depolarization in sinus nodal cells and has a key role in heartbeat generation. Therefore, we hypothesized that some forms of \"idiopathic\" sinus node dysfunction (SND) are related to inherited dysfunctions of cardiac pacemaker ion channels. In a candidate gene approach, a heterozygous 1-bp deletion (1631delC) in exon 5 of the human HCN4 gene was detected in a patient with idiopathic SND. The mutant HCN4 protein (HCN4-573X) had a truncated C-terminus and lacked the cyclic nucleotide-binding domain. COS-7 cells transiently transfected with HCN4-573X cDNA indicated normal intracellular trafficking and membrane integration of HCN4-573X subunits. Patch-clamp experiments showed that HCN4-573X channels mediated I(f)-like currents that were insensitive to increased cellular cAMP levels. Coexpression experiments showed a dominant-negative effect of HCN4-573X subunits on wild-type subunits. These data indicate that the cardiac I(f) channels are functionally expressed but with altered biophysical properties. Taken together, the clinical, genetic, and in vitro data provide a likely explanation for the patient's sinus bradycardia and the chronotropic incompetence." ], "offsets": [ [ 68, 1308 ] ] } ]

[ { "id": "1931", "type": "DNAMutation", "text": [ "1631delC" ], "offsets": [ [ 440, 448 ] ], "normalized": [] } ]

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[ { "id": "1935", "type": "title", "text": [ "Genetic changes and expression of the mannose 6-phosphate/insulin-like growth factor II receptor gene in human hepatitis B virus-associated hepatocellular carcinoma." ], "offsets": [ [ 0, 165 ] ] }, { "id": "1936", "type": "abstract", "text": [ "It was reported that 60-70% of hepatitis B virus (HBV)-negative hepatocellular carcinoma (HCC) had loss of heterozygosity (LOH) at the mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) locus and this gene was mutated in 55% of these patients with LOH. In this study, genomic DNA from 29 pairs of HBV-positive HCC and corresponding non-tumor tissues was used to analyze LOH at the M6P/IGF2R locus and single deoxyguanosine deletion in this gene by PCR. Total RNA from 19 of the 29 patients was utilized to determine a 192 bp insert in the M6P/IGF2R mRNA and expression of this gene by RT-PCR. Twenty-eight of 29 (97%) HBV-positive HCC were found to be informative at the M6P/IGF2R locus but LOH at this region was only detected in 4/28 (14%) informative patients. Neither single deoxyguanosine deletion in this gene nor 192 bp insert in its mRNA occurred in these patients. Compared with corresponding non-tumor tissues, expression of the M6P/IGF2R mRNA was decreased in 13/19 (68%) HBV-positive HCC tissues, suggesting that M6P/IGF2R may be involved in HBV-associated hepatocarcinogenesis by the regulation of its expression level. In the development of HBV-associated HCC, M6P/IGF2R mutation may not be a major agent." ], "offsets": [ [ 166, 1405 ] ] } ]

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[ { "id": "1942", "type": "title", "text": [ "NRAMP1 genetic polymorphisms as a risk factor of tuberculous pleurisy." ], "offsets": [ [ 0, 70 ] ] }, { "id": "1943", "type": "abstract", "text": [ "SETTING: Nrampl encoded by the NRAMP1 gene influences the phagolysosomal function of alveolar macrophage against Mycobacterium tuberculosis. Genetic polymorphisms of NRAMP1 affect innate host resistance through the defective production and function of Nrampl. OBJECTIVE: To investigate this relationship, the NRAMP1 polymorphisms in patients with tuberculous pleurisy were determined. DESIGN: Pleural biopsy proven 56 patients were designated to the pleurisy group and 45 healthy adults were designated to the healthy control group. Three NRAMP1 polymorphisms such as single nucleotide change in intron 4(469 + 14G/C, INT4), a non-conservative single-base substitution at codon 543(D543N) and TGTG deletion in the 3' untranslated region (1729 + 55del4, 3'UTR) were determined. RESULTS: The frequencies of mutant genotypes of INT4 and 3'UTR were significantly high in the pleurisy group (P = 0.01, P = 0.02), but the frequencies of D543N were not significantly different between the two groups. Odds ratios (OR), which are a comparison of the wild with the mutant genotype, were 8.02 (95%CI 2.42 approximately 26.57) for INT4 and 5.73 (95%CI 1.14 approximately 28.92) for 3'UTR which were statistically significant. In the combined analysis of the INT4 and 3'UTR, the ORs were 6.00 (95%CI 1.46 approximately 24.64) for GC/++ genotype and 14.00 (95%CI 1.61 approximately 121.75) for GC/+del when compared with GG/++; these differences were statistically significant. CONCLUSION: The NRAMP1 genetic polymorphisms, especially INT4 and 3'UTR, were closely related to tuberculous pleurisy." ], "offsets": [ [ 71, 1654 ] ] } ]

[ { "id": "1938", "type": "DNAMutation", "text": [ "469 + 14G/C" ], "offsets": [ [ 676, 687 ] ], "normalized": [] }, { "id": "1939", "type": "ProteinMutation", "text": [ "D543N" ], "offsets": [ [ 753, 758 ] ], "normalized": [] }, { "id": "1940", "type": "DNAMutation", "text": [ "1729 + 55del4" ], "offsets": [ [ 809, 822 ] ], "normalized": [] }, { "id": "1941", "type": "ProteinMutation", "text": [ "D543N" ], "offsets": [ [ 1002, 1007 ] ], "normalized": [] } ]

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[ { "id": "1945", "type": "title", "text": [ "A novel CACNA1F mutation in a french family with the incomplete type of X-linked congenital stationary night blindness." ], "offsets": [ [ 0, 119 ] ] }, { "id": "1946", "type": "abstract", "text": [ "PURPOSE: To describe a French family with the incomplete type of X-linked congenital stationary night blindness (CSNB2) associated with a novel mutation in the retina-specific calcium channel alpha(1) subunit gene (CACNA1F). DESIGN: Interventional case report. METHODS: Two family members with a history of nonprogressive night blindness and subnormal visual acuity were clinically examined and the genotype determined by molecular genetic analysis. RESULT: Both patients had clinical manifestations characteristic of CSNB2. Electrophysiologically, we found a predominant reduction of the ERG B-wave in the maximal response. Both rod and cone function were subnormal, with the latter tending to be more attenuated. We identified a C deletion at nucleotide position 4548, resulting in a frameshift with a predicted premature termination at codon 1524. CONCLUSIONS: The clinical and genetic study of a novel mutation in the CACNA1F gene adds further support to the contention that CSNB2 represents a genetically distinct retinal disorder of a calcium channel." ], "offsets": [ [ 120, 1177 ] ] } ]

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[ { "id": "1954", "type": "title", "text": [ "Analysis of the G/C polymorphism in the 5'-untranslated region of the RAD51 gene in breast cancer." ], "offsets": [ [ 0, 98 ] ] }, { "id": "1955", "type": "abstract", "text": [ "The breast cancer suppressor proteins BRCA1 and BRCA2 interact with RAD51, a protein essential for maintaining genomic stability by playing a central role in homology-dependent recombinational repair of the DNA double-strand breaks. Therefore, genetic variability in the RAD51 gene may contribute to the appearance and/or progression of breast cancer. A single nucleotide polymorphism in the 5'- untranslated region of RAD51 (a G to C substitution at position 135, the G/C polymorphism) is reported to modulate breast cancer risk. We investigated the distribution of genotypes and frequency of alleles of the G/C polymorphism in breast cancer. Tumor tissues were obtained from postmenopausal women with node-negative and node-positive breast carcinoma with uniform tumor size. Blood samples from age matched healthy women served as control. The G/C polymorphism was determined by PCR-based MvaI restriction fragment length polymorphism. The distribution of the genotypes of the G/C polymorphism did not differ significantly (P > 0.05) from those predicted by the Hardy-Weinberg distribution. There were no differences in the genotype distribution and allele frequencies between node-positive and node-negative patients. There were no significant differences between distributions of the genotypes in subgroups assigned to histological grades according to Scarf-Bloom-Richardson criteria and the distribution predicted by Hardy-Weinberg equilibrium (P > 0.05). Our study implies that the G/C polymorphism of the RAD51 gene may not be directly involved in the development and/or progression of breast cancer and so it may not be useful as an independent marker in this disease." ], "offsets": [ [ 99, 1774 ] ] } ]

[ { "id": "1948", "type": "DNAMutation", "text": [ "G/C" ], "offsets": [ [ 16, 19 ] ], "normalized": [] }, { "id": "1949", "type": "DNAMutation", "text": [ "G/C" ], "offsets": [ [ 568, 571 ] ], "normalized": [] }, { "id": "1950", "type": "DNAMutation", "text": [ "G/C" ], "offsets": [ [ 708, 711 ] ], "normalized": [] }, { "id": "1951", "type": "DNAMutation", "text": [ "G/C" ], "offsets": [ [ 944, 947 ] ], "normalized": [] }, { "id": "1952", "type": "DNAMutation", "text": [ "G/C" ], "offsets": [ [ 1077, 1080 ] ], "normalized": [] }, { "id": "1953", "type": "DNAMutation", "text": [ "G/C" ], "offsets": [ [ 1586, 1589 ] ], "normalized": [] } ]

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[ { "id": "1957", "type": "title", "text": [ "Mutation analysis of DMBT1 in glioblastoma, medulloblastoma and oligodendroglial tumors." ], "offsets": [ [ 0, 88 ] ] }, { "id": "1958", "type": "abstract", "text": [ "DMBT1 has been implicated as a candidate tumor suppressor gene on chromosome 10q for brain, gastrointestinal and lung cancer. Homozygous deletion and lack of expression are 2 known mechanisms for inactivating DMBT1. We evaluated whether somatic mutation, which represents a major inactivation mechanism for most tumor suppressor genes, occurs in the DMBT1 gene. A total of 102 primary brain tumors, consisting of 25 glioblastoma multiforme, 24 medulloblastoma and 53 oligodendroglial tumors, were analyzed by conformation-sensitive gel electrophoresis in all 54 coding exons of DMBT1. Twelve different base substitutions were detected in 26 (25%) tumors. Eight base substitutions resulted in amino acid changes and 4 were silent. These base changes were also detected in tumor-matched blood samples, however, indicating that the base variations represent genetic polymorphisms. We also assessed homozygous deletions of the DMBT1 gene in the series and found that 16 of 95 (5 glioblastomas, 5 medulloblastomas, 6 oligodendroglial tumors; total 17%) tumors harbor such alteration. High-quality blood DNA samples were available in 5 tumors carrying homozygous deletion and, using long-range PCR, 3 of these blood samples showed germline hemizygous deletions in a region between introns 10 and 26 of DMBT1. Our results showed that mutation does not play a role in inactivation of DMBT1 in brain tumors. Intragenic homozygous deletion of DMBT1 is common in brain tumors and is likely a result of a germline deletion of 1 allele followed by loss of the second allele during tumor development." ], "offsets": [ [ 89, 1675 ] ] } ]

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[ { "id": "1960", "type": "title", "text": [ "Relation of shyness in grade school children to the genotype for the long form of the serotonin transporter promoter region polymorphism." ], "offsets": [ [ 0, 137 ] ] }, { "id": "1961", "type": "abstract", "text": [ "OBJECTIVE: Studies have shown that genetic factors are significant in predisposing individuals to shyness and social phobia. Toward further elucidating the genetic structure of shyness, the authors examined four functional polymorphisms that make biological sense for contributing to the development of this phenotype: serotonin transporter promoter region 44 base pair insertion/deletion (5-HTTLPR), dopamine D(4) receptor exon III repeat (DRD4), catechol O-methyltransferase (COMT), and monoamine oxidase A promoter region repeat (MAO(A)). METHOD: The authors assessed shyness after recruitment of a nonclinical sample (N=118, unscreened second-grade children) using a composite scale derived from questionnaires administered to the children, parents, and teachers. DNA from buccal smears successfully obtained from 98 children was genotyped by polymerase chain reaction methods for the 5-HTTLPR, DRD4, COMT, and MAO(A) polymorphisms. RESULTS: Significant correlations were observed for parents', teachers', and children's ratings of shyness, and Cronbach's alpha reliability was high for all three scales. A significant association was observed between the long 5-HTTLPR polymorphism and shyness, both by the functional classification of Lesch as well as by consideration of all three genotypes. No significant association was observed for the DRD4, COMT, or MAO(A) polymorphisms. CONCLUSIONS: This study provisionally identifies a common genetic polymorphism, 5-HTTLPR, that modestly (effect size=7%) contributed to greater shyness scores in a nonclinical group of second-grade students. These first findings may be relevant to previous reports that have shown an association between the 5-HTTLPR long form and obsessive-compulsive disorder and autism." ], "offsets": [ [ 138, 1894 ] ] } ]

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[ { "id": "1967", "type": "title", "text": [ "Restricted genetic defects underlie human complement C6 deficiency." ], "offsets": [ [ 0, 67 ] ] }, { "id": "1968", "type": "abstract", "text": [ "Complement C6 homozygous deficiency (C6D) has been rarely observed in Caucasians but was reported at higher prevalence among African-Americans. We report on the molecular basis of C6D in seven unrelated black individuals of North or Central Africa descent who live in France. These patients have presented Neisseria meningitidis infection (four cases), focal and segmental glomerulosclerosis with hyalinosis (one case), systemic lupus erythematosus (one case) or Still's disease (one case). All patients exhibited undetectable antigenic C6 by using a sensitive ELISA assay. An additional four cases of complete C6 deficiency with no associated disease have been characterized after family studies. Exons 6, 7 and 12 have been described recently as the location of molecular defects on the C6 gene in randomly chosen black Americans. Genomic DNA from the seven patients were subjected to direct polymerase chain reaction amplification of these three exons. Nucleotide sequencing analysis of the amplified DNA fragments revealed a homozygous single-base deletion (1936delG) in exon 12 in three cases and four compound heterozygous deletions for a single base in exon 7 (1195delC) or in exon 6 (878delA) associated with the same deletion in exon 12 (1936delG). Our observations further establish the restricted pattern of genetic defects associated with homozygous C6 complement deficiency in individuals of African descent." ], "offsets": [ [ 68, 1489 ] ] } ]

[ { "id": "1963", "type": "DNAMutation", "text": [ "1936delG" ], "offsets": [ [ 1130, 1138 ] ], "normalized": [] }, { "id": "1964", "type": "DNAMutation", "text": [ "1195delC" ], "offsets": [ [ 1236, 1244 ] ], "normalized": [] }, { "id": "1965", "type": "DNAMutation", "text": [ "878delA" ], "offsets": [ [ 1260, 1267 ] ], "normalized": [] }, { "id": "1966", "type": "DNAMutation", "text": [ "1936delG" ], "offsets": [ [ 1315, 1323 ] ], "normalized": [] } ]

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