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[ { "id": "11799475__text", "type": "abstract", "text": [ "Evidence for a susceptibility gene for anorexia nervosa on chromosome 1. Eating disorders, such as anorexia nervosa (AN), have a significant genetic component. In the current study, a genomewide linkage analysis of 192 families with at least one affected relative pair with AN and related eating disorders, including bulimia nervosa, was performed, resulting in only modest evidence for linkage, with the highest nonparametric linkage (NPL) score, 1.80, at marker D4S2367 on chromosome 4. Since the reduction of sample heterogeneity would increase power to detect linkage, we performed linkage analysis in a subset (n=37) of families in which at least two affected relatives had diagnoses of restricting AN, a clinically defined subtype of AN characterized by severe limitation of food intake without the presence of binge-eating or purging behavior. When we limited the linkage analysis to this clinically more homogeneous subgroup, the highest multipoint NPL score observed was 3.03, at marker D1S3721 on chromosome 1p. The genotyping of additional markers in this region led to a peak multipoint NPL score of 3.45, thereby providing suggestive evidence for the presence of an AN-susceptibility locus on chromosome 1p.\n" ], "offsets": [ [ 0, 1221 ] ] } ]

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[ { "id": "12145742__text", "type": "abstract", "text": [ "Neuregulin 1 and susceptibility to schizophrenia. The cause of schizophrenia is unknown, but it has a significant genetic component. Pharmacologic studies, studies of gene expression in man, and studies of mouse mutants suggest involvement of glutamate and dopamine neurotransmitter systems. However, so far, strong association has not been found between schizophrenia and variants of the genes encoding components of these systems. Here, we report the results of a genomewide scan of schizophrenia families in Iceland; these results support previous work, done in five populations, showing that schizophrenia maps to chromosome 8p. Extensive fine-mapping of the 8p locus and haplotype-association analysis, supplemented by a transmission/disequilibrium test, identifies neuregulin 1 (NRG1) as a candidate gene for schizophrenia. NRG1 is expressed at central nervous system synapses and has a clear role in the expression and activation of neurotransmitter receptors, including glutamate receptors. Mutant mice heterozygous for either NRG1 or its receptor, ErbB4, show a behavioral phenotype that overlaps with mouse models for schizophrenia. Furthermore, NRG1 hypomorphs have fewer functional NMDA receptors than wild-type mice. We also demonstrate that the behavioral phenotypes of the NRG1 hypomorphs are partially reversible with clozapine, an atypical antipsychotic drug used to treat schizophrenia.\n" ], "offsets": [ [ 0, 1405 ] ] } ]

[ { "id": "12145742_T1", "type": "Gene", "text": [ "NRG1" ], "offsets": [ [ 785, 789 ] ], "normalized": [] }, { "id": "12145742_T2", "type": "Gene", "text": [ "neuregulin 1" ], "offsets": [ [ 771, 783 ] ], "normalized": [] }, { "id": "12145742_T3", "type": "Gene", "text": [ "NRG1" ], "offsets": [ [ 830, 834 ] ], "normalized": [] }, { "id": "12145742_T4", "type": "Gene", "text": [ "NRG1" ], "offsets": [ [ 1035, 1039 ] ], "normalized": [] }, { "id": "12145742_T5", "type": "Gene", "text": [ "NRG1" ], "offsets": [ [ 1156, 1160 ] ], "normalized": [] }, { "id": "12145742_T6", "type": "Gene", "text": [ "NRG1" ], "offsets": [ [ 1288, 1292 ] ], "normalized": [] } ]

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[ { "id": "12145742_R1", "type": "Equals", "arg1_id": "12145742_T2", "arg2_id": "12145742_T1", "normalized": [] } ]

[ { "id": "12016592__text", "type": "abstract", "text": [ "Intron-size constraint as a mutational mechanism in Rothmund-Thomson syndrome. Rothmund-Thomson syndrome (RTS) is an autosomal recessive disorder caused by deleterious mutations in the RECQL4 gene on chromosome 8. The RECQL4 gene structure is unusual because it contains many small introns <100 bp. We describe a proband with RTS who has a novel 11-bp intronic deletion, and we show that this mutation results in a 66-bp intron too small for proper splicing. Constraint on intron size may represent a general mutational mechanism, since human-genome analysis reveals that approximately 15% of genes have introns <100 bp and are therefore susceptible to size constraint. Thus, monitoring of intron size may allow detection of mutations missed by exon-by-exon approaches.\n" ], "offsets": [ [ 0, 770 ] ] } ]

[ { "id": "12016592_T1", "type": "Gene", "text": [ "RECQL4" ], "offsets": [ [ 185, 191 ] ], "normalized": [] }, { "id": "12016592_T2", "type": "Gene", "text": [ "RECQL4" ], "offsets": [ [ 218, 224 ] ], "normalized": [] } ]

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[ { "id": "12080485__text", "type": "abstract", "text": [ "Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), also known as \"Nasu-Hakola disease,\" is a globally distributed recessively inherited disease leading to death during the 5th decade of life and is characterized by early-onset progressive dementia and bone cysts. Elsewhere, we have identified PLOSL mutations in TYROBP (DAP12), which codes for a membrane receptor component in natural-killer and myeloid cells, and also have identified genetic heterogeneity in PLOSL, with some patients carrying no mutations in TYROBP. Here we complete the molecular pathology of PLOSL by identifying TREM2 as the second PLOSL gene. TREM2 forms a receptor signaling complex with TYROBP and triggers activation of the immune responses in macrophages and dendritic cells. Patients with PLOSL have no defects in cell-mediated immunity, suggesting a remarkable capacity of the human immune system to compensate for the inactive TYROBP-mediated activation pathway. Our data imply that the TYROBP-mediated signaling pathway plays a significant role in human brain and bone tissue and provide an interesting example of how mutations in two different subunits of a multisubunit receptor complex result in an identical human disease phenotype.\n" ], "offsets": [ [ 0, 1380 ] ] } ]

[ { "id": "12080485_T1", "type": "Gene", "text": [ "TYROBP" ], "offsets": [ [ 473, 479 ] ], "normalized": [] }, { "id": "12080485_T2", "type": "Gene", "text": [ "DAP12" ], "offsets": [ [ 481, 486 ] ], "normalized": [] }, { "id": "12080485_T3", "type": "Gene", "text": [ "TYROBP" ], "offsets": [ [ 673, 679 ] ], "normalized": [] }, { "id": "12080485_T4", "type": "Gene", "text": [ "TREM2" ], "offsets": [ [ 746, 751 ] ], "normalized": [] }, { "id": "12080485_T5", "type": "Gene", "text": [ "TREM2" ], "offsets": [ [ 778, 783 ] ], "normalized": [] }, { "id": "12080485_T6", "type": "Gene", "text": [ "TYROBP" ], "offsets": [ [ 824, 830 ] ], "normalized": [] }, { "id": "12080485_T7", "type": "Gene", "text": [ "TYROBP" ], "offsets": [ [ 1069, 1075 ] ], "normalized": [] }, { "id": "12080485_T8", "type": "Gene", "text": [ "TYROBP" ], "offsets": [ [ 1129, 1135 ] ], "normalized": [] } ]

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[ { "id": "12080485_R1", "type": "Equals", "arg1_id": "12080485_T1", "arg2_id": "12080485_T2", "normalized": [] } ]

[ { "id": "11951177__text", "type": "abstract", "text": [ "High-throughput analysis of subtelomeric chromosome rearrangements by use of array-based comparative genomic hybridization. Telomeric chromosome rearrangements may cause mental retardation, congenital anomalies, and miscarriages. Automated detection of subtle deletions or duplications involving telomeres is essential for high-throughput diagnosis, but impossible when conventional cytogenetic methods are used. Array-based comparative genomic hybridization (CGH) allows high-resolution screening of copy number abnormalities by hybridizing differentially labeled test and reference genomes to arrays of robotically spotted clones. To assess the applicability of this technique in the diagnosis of (sub)telomeric imbalances, we here describe a blinded study, in which DNA from 20 patients with known cytogenetic abnormalities involving one or more telomeres was hybridized to an array containing a validated set of human-chromosome-specific (sub)telomere probes. Single-copy-number gains and losses were accurately detected on these arrays, and an excellent concordance between the original cytogenetic diagnosis and the array-based CGH diagnosis was obtained by use of a single hybridization. In addition to the previously identified cytogenetic changes, array-based CGH revealed additional telomere rearrangements in 3 of the 20 patients studied. The robustness and simplicity of this array-based telomere copy-number screening make it highly suited for introduction into the clinic as a rapid and sensitive automated diagnostic procedure.\n" ], "offsets": [ [ 0, 1543 ] ] } ]

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[ { "id": "12145749__text", "type": "abstract", "text": [ "Order of intron removal influences multiple splice outcomes, including a two-exon skip, in a COL5A1 acceptor-site mutation that results in abnormal pro-alpha1(V) N-propeptides and Ehlers-Danlos syndrome type I. Ehlers-Danlos syndrome (EDS) type I (the classical variety) is a dominantly inherited, genetically heterogeneous connective-tissue disorder. Mutations in the COL5A1 and COL5A2 genes, which encode type V collagen, have been identified in several individuals. Most mutations affect either the triple-helical domain of the protein or the expression of one COL5A1 allele. We identified a novel splice-acceptor mutation (IVS4-2A-->G) in the N-propeptide-encoding region of COL5A1, in one patient with EDS type I. The outcome of this mutation was complex: In the major product, both exons 5 and 6 were skipped; other products included a small amount in which only exon 5 was skipped and an even smaller amount in which cryptic acceptor sites within exon 5 were used. All products were in frame. Pro-alpha1(V) chains with abnormal N-propeptides were secreted and were incorporated into extracellular matrix, and the mutation resulted in dramatic alterations in collagen fibril structure. The two-exon skip occurred in transcripts in which intron 5 was removed rapidly relative to introns 4 and 6, leaving a large (270 nt) composite exon that can be skipped in its entirety. The transcripts in which only exon 5 was skipped were derived from those in which intron 6 was removed prior to intron 5. The use of cryptic acceptor sites in exon 5 occurred in transcripts in which intron 4 was removed subsequent to introns 5 and 6. These findings suggest that the order of intron removal plays an important role in the outcome of splice-site mutations and provide a model that explains why multiple products derive from a mutation at a single splice site.\n" ], "offsets": [ [ 0, 1853 ] ] } ]

[ { "id": "12145749_T1", "type": "Gene", "text": [ "COL5A1" ], "offsets": [ [ 93, 99 ] ], "normalized": [] }, { "id": "12145749_T2", "type": "Gene", "text": [ "COL5A1" ], "offsets": [ [ 369, 375 ] ], "normalized": [] }, { "id": "12145749_T3", "type": "Gene", "text": [ "COL5A2" ], "offsets": [ [ 380, 386 ] ], "normalized": [] }, { "id": "12145749_T4", "type": "Gene", "text": [ "COL5A1" ], "offsets": [ [ 564, 570 ] ], "normalized": [] }, { "id": "12145749_T5", "type": "Gene", "text": [ "COL5A1" ], "offsets": [ [ 679, 685 ] ], "normalized": [] }, { "id": "12145749_T6", "type": "SNP", "text": [ "IVS4-2A-->G" ], "offsets": [ [ 627, 638 ] ], "normalized": [] } ]

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[ { "id": "12145749_R1", "type": "AssociatedTo", "arg1_id": "12145749_T6", "arg2_id": "12145749_T5", "normalized": [] } ]

[ { "id": "11813133__text", "type": "abstract", "text": [ "A polymorphism in the human UGRP1 gene promoter that regulates transcription is associated with an increased risk of asthma. Several traits associated with asthma phenotypes, such as high total serum immunoglobulin E and bronchial hyperresponsiveness, have been linked by numerous genome-screen studies and linkage analyses to markers on human chromosome 5q31-q34. In the present article, we describe UGRP1 (encoding uteroglobin-related protein 1) as one of asthma-susceptibility genes that is located on chromosome 5q31-q32. UGRP1 is a homodimeric secretory protein of 17 kDa and is expressed only in lung and trachea. The G --> A polymorphism was identified at -112 bp in the human UGRP1 gene promoter. The -112A allele is responsible for a 24% reduction in the promoter activity in relation to the -112G allele, as examined by transfection analysis. Electrophoretic mobility-shift analysis revealed that an unknown nuclear factor binds to the region around -112 bp. The binding affinity with the -112A oligonucleotide was reduced by approximately one half, as compared with the -112G oligonucleotide. In a case-control study using 169 Japanese individuals (84 patients with asthma and 85 healthy control individuals), those with a -112A allele (G/A or A/A) were 4.1 times more likely to have asthma than were those with the wild-type allele (G/G).\n" ], "offsets": [ [ 0, 1351 ] ] } ]

[ { "id": "11813133_T1", "type": "Gene", "text": [ "UGRP1" ], "offsets": [ [ 28, 33 ] ], "normalized": [] }, { "id": "11813133_T2", "type": "Gene", "text": [ "UGRP1" ], "offsets": [ [ 401, 406 ] ], "normalized": [] }, { "id": "11813133_T3", "type": "Gene", "text": [ "uteroglobin-related protein 1" ], "offsets": [ [ 417, 446 ] ], "normalized": [] }, { "id": "11813133_T4", "type": "Gene", "text": [ "UGRP1" ], "offsets": [ [ 526, 531 ] ], "normalized": [] }, { "id": "11813133_T5", "type": "Gene", "text": [ "UGRP1" ], "offsets": [ [ 684, 689 ] ], "normalized": [] }, { "id": "11813133_T6", "type": "SNP", "text": [ "G --> A polymorphism was identified at -112 bp" ], "offsets": [ [ 624, 670 ] ], "normalized": [] } ]

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[ { "id": "11731936__text", "type": "abstract", "text": [ "Human-specific duplication and mosaic transcripts: the recent paralogous structure of chromosome 22. In recent decades, comparative chromosomal banding, chromosome painting, and gene-order studies have shown strong conservation of gross chromosome structure and gene order in mammals. However, findings from the human genome sequence suggest an unprecedented degree of recent (<35 million years ago) segmental duplication. This dynamism of segmental duplications has important implications in disease and evolution. Here we present a chromosome-wide view of the structure and evolution of the most highly homologous duplications (> or = 1 kb and > or = 90%) on chromosome 22. Overall, 10.8% (3.7/33.8 Mb) of chromosome 22 is duplicated, with an average sequence identity of 95.4%. To organize the duplications into tractable units, intron-exon structure and well-defined duplication boundaries were used to define 78 duplicated modules (minimally shared evolutionary segments) with 157 copies on chromosome 22. Analysis of these modules provides evidence for the creation or modification of 11 novel transcripts. Comparative FISH analyses of human, chimpanzee, gorilla, orangutan, and macaque reveal qualitative and quantitative differences in the distribution of these duplications--consistent with their recent origin. Several duplications appear to be human specific, including a approximately 400-kb duplication (99.4%-99.8% sequence identity) that transposed from chromosome 14 to the most proximal pericentromeric region of chromosome 22. Experimental and in silico data further support a pericentromeric gradient of duplications where the most recent duplications transpose adjacent to the centromere. Taken together, these data suggest that segmental duplications have been an ongoing process of primate genome evolution, contributing to recent gene innovation and the dynamic transformation of genome architecture within and among closely related species.\n" ], "offsets": [ [ 0, 1965 ] ] } ]

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[ { "id": "12515255__text", "type": "abstract", "text": [ "The ABCA4 gene in autosomal recessive cone-rod dystrophies.\n" ], "offsets": [ [ 0, 60 ] ] } ]

[ { "id": "12515255_T1", "type": "Gene", "text": [ "ABCA4" ], "offsets": [ [ 4, 9 ] ], "normalized": [] } ]

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[ { "id": "11951176__text", "type": "abstract", "text": [ "Quantitative trait loci on chromosomes 1, 2, 3, 4, 8, 9, 11, 12, and 18 control variation in levels of T and B lymphocyte subpopulations. Lymphocyte subpopulation levels are used for prognosis and monitoring of a variety of human diseases, especially those with an infectious etiology. As a primary step to defining the major gene variation underlying these phenotypes, we conducted the first whole-genome screen for quantitative variation in lymphocyte count, CD4 T cell, CD8 T cell, B cell, and natural killer cell numbers, as well as CD4:CD8 ratio. The screen was performed in 15 of the CEPH families that form the main human genome genetic project mapping resource. Quantitative-trait loci (QTLs) that account for significant proportions of the phenotypic variance of lymphocyte subpopulations were detected on chromosomes 1, 2, 3, 4, 8, 9, 11, 12, and 18. The most significant QTL found was for CD4 levels on chromosome 8 (empirical P=.00005). Two regions of chromosome 4 showed significant linkage to CD4:CD8 ratio (empirical P=.00007 and P=.003). A QTL for the highly correlated measures of CD4 and CD19 levels colocalized at 18q21 (both P=.003). Similarly, a shared region of chromosome 1 was linked to CD8 and CD19 levels (P=.0001 and P=.002, respectively). Several of the identified chromosome regions are likely to harbor polymorphic candidate genes responsible for these important human phenotypes. Their discovery has important implications for understanding the generation of the immune repertoire and understanding immune-system homeostasis. More generally, these data show the power of an integrated human gene-mapping approach for heritable molecular phenotypes, using large pedigrees that have been extensively genotyped.\n" ], "offsets": [ [ 0, 1740 ] ] } ]

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[ { "id": "12384858__text", "type": "abstract", "text": [ "The fingerprint of phantom mutations in mitochondrial DNA data. Phantom mutations are systematic artifacts generated in the course of the sequencing process itself. In sequenced mitochondrial DNA (mtDNA), they generate a hotspot pattern quite different from that of natural mutations in the cell. To identify the telltale patterns of a particular phantom mutation process, one first filters out the well-established frequent mutations (inferred from various data sets with additional coding region information). The filtered data are represented by their full (quasi-)median network, to visualize the character conflicts, which can be expressed numerically by the cube spectrum. Permutation tests are used to evaluate the overall phylogenetic content of the filtered data. Comparison with benchmark data sets helps to sort out suspicious data and to infer features and potential causes for the phantom mutation process. This approach, performed either in the lab or at the desk of a reviewer, will help to avoid errors that otherwise would go into print and could lead to erroneous evolutionary interpretations. The filtering procedure is illustrated with two mtDNA data sets that were severely affected by phantom mutations.\n" ], "offsets": [ [ 0, 1226 ] ] } ]

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[ { "id": "12145747__text", "type": "abstract", "text": [ "Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. Tibial muscular dystrophy (TMD) is an autosomal dominant late-onset distal myopathy linked to chromosome 2q31. The linked region includes the giant TTN gene, which encodes the central sarcomeric protein, titin. We have previously shown a secondary calpain-3 defect to be associated with TMD, which further underscored that titin is the candidate. We now report the first mutations in TTN to cause a human skeletal-muscle disease, TMD. In Mex6, the last exon of TTN, a unique 11-bp deletion/insertion mutation, changing four amino acid residues, completely cosegregated with all tested 81 Finnish patients with TMD in 12 unrelated families. The mutation was not found in 216 Finnish control samples. In a French family with TMD, a Leu-->Pro mutation at position 293,357 in Mex6 was discovered. Mex6 is adjacent to the known calpain-3 binding site Mex5 of M-line titin. Immunohistochemical analysis using two exon-specific antibodies directed to the M-line region of titin demonstrated the specific loss of carboxy-terminal titin epitopes in the TMD muscle samples that we studied, thus implicating a functional defect of the M-line titin in the genesis of the TMD disease phenotype.\n" ], "offsets": [ [ 0, 1312 ] ] } ]

[ { "id": "12145747_T1", "type": "Gene", "text": [ "TTN" ], "offsets": [ [ 66, 69 ] ], "normalized": [] }, { "id": "12145747_T2", "type": "Gene", "text": [ "TTN" ], "offsets": [ [ 278, 281 ] ], "normalized": [] }, { "id": "12145747_T3", "type": "Gene", "text": [ "TTN" ], "offsets": [ [ 514, 517 ] ], "normalized": [] }, { "id": "12145747_T4", "type": "Gene", "text": [ "TTN" ], "offsets": [ [ 591, 594 ] ], "normalized": [] }, { "id": "12145747_T5", "type": "SNP", "text": [ "Leu-->Pro mutation at position 293,357" ], "offsets": [ [ 860, 898 ] ], "normalized": [] }, { "id": "12145747_T6", "type": "Gene", "text": [ "Mex6" ], "offsets": [ [ 902, 906 ] ], "normalized": [] }, { "id": "12145747_T7", "type": "Gene", "text": [ "Mex6" ], "offsets": [ [ 923, 927 ] ], "normalized": [] }, { "id": "12145747_T8", "type": "Gene", "text": [ "Mex5" ], "offsets": [ [ 976, 980 ] ], "normalized": [] } ]

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[ { "id": "12145747_R1", "type": "AssociatedTo", "arg1_id": "12145747_T5", "arg2_id": "12145747_T6", "normalized": [] } ]

[ { "id": "11781875__text", "type": "abstract", "text": [ "2001 ASHG Award for Excellence in Education. Introductory speech for Charles Scriver.\n" ], "offsets": [ [ 0, 86 ] ] } ]

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[ { "id": "11992269__text", "type": "abstract", "text": [ "The power of multivariate quantitative-trait loci linkage analysis is influenced by the correlation between variables.\n" ], "offsets": [ [ 0, 119 ] ] } ]

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[ { "id": "11822023__text", "type": "abstract", "text": [ "Evidence of genetic interaction between the beta-globin complex and chromosome 8q in the expression of fetal hemoglobin. During human development, the switch from fetal to adult hemoglobin (Hb) is not complete with the residual gamma-globin expression being restricted to a subset of erythrocytes termed \"F cells\" (FC). Statistical analyses have shown the FC trait to be influenced by a common sequence variant (C-->T) at position -158 upstream of the Ggamma-globin gene, termed the \"XmnI-Ggamma polymorphism.\" The XmnI-Ggamma site is believed to be involved in the expression of the Ggamma-globin gene through interaction with transcription factors, and polymorphisms in the transcription factors could be influencing fetal Hb expression, conditional on the XmnI-Ggamma site. Using a two-locus model, in which the second locus was the known quantitative-trait locus (QTL) at the XmnI-Ggamma site, we showed suggestive linkage to chromosome 8q. A maximum single-point LOD score of 4.33 and a multipoint LOD score of 4.75 were found in a 15-20 cM region of chromosome 8q. A single-locus analysis failed to show linkage of FC to the region when the XmnI-Ggamma site was accounted for by removing its effects from the data or including it as a covariate. Results of the single-locus analysis were significant when the effects of the XmnI-Ggamma site were not accounted for in any way. The results of analysis in a large Indian kindred indicate that there is an interaction between the XmnI-Ggamma site and a QTL on chromosome 8q that is influencing the production of fetal Hb.\n" ], "offsets": [ [ 0, 1574 ] ] } ]

[ { "id": "11822023_T1", "type": "Gene", "text": [ "Ggamma-globin" ], "offsets": [ [ 452, 465 ] ], "normalized": [] }, { "id": "11822023_T2", "type": "SNP", "text": [ "(C-->T) at position -158 upstream" ], "offsets": [ [ 411, 444 ] ], "normalized": [] }, { "id": "11822023_T3", "type": "Gene", "text": [ "Ggamma-globin" ], "offsets": [ [ 584, 597 ] ], "normalized": [] } ]

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[ { "id": "11822023_R1", "type": "AssociatedTo", "arg1_id": "11822023_T2", "arg2_id": "11822023_T1", "normalized": [] } ]

[ { "id": "12145744__text", "type": "abstract", "text": [ "The Xq22 inversion breakpoint interrupted a novel Ras-like GTPase gene in a patient with Duchenne muscular dystrophy and profound mental retardation. A male patient with profound mental retardation, athetosis, nystagmus, and severe congenital hypotonia (Duchenne muscular dystrophy [DMD]) was previously shown to carry a pericentric inversion of the X chromosome, 46,Y,inv(X)(p21.2q22.2). His mother carried this inversion on one X allele. The patient's condition was originally misdiagnosed as cerebral palsy, and only later was it diagnosed as DMD. Because the DMD gene is located at Xp21.2, which is one breakpoint of the inv(X), and because its defects are rarely associated with severe mental retardation, the other clinical features of this patient were deemed likely to be associated with the opposite breakpoint at Xq22. Our precise molecular-cytogenetic characterization of both breakpoints revealed three catastrophic genetic events that had probably influenced neuromuscular and cognitive development: deletion of part of the DMD gene at Xp21.2, duplication of the human proteolipid protein gene (PLP) at Xq22.2, and disruption of a novel gene. The latter sequence, showing a high degree of homology to the Sec4 gene of yeast, encoded a putative small guanine-protein, Ras-like GTPase that we have termed \"RLGP.\" Immunocytochemistry located RLGP at mitochondria. We speculate that disruption of RLGP was responsible for the patient's profound mental retardation.\n" ], "offsets": [ [ 0, 1474 ] ] } ]

[ { "id": "12145744_T3", "type": "Gene", "text": [ "human proteolipid protein" ], "offsets": [ [ 1076, 1101 ] ], "normalized": [] }, { "id": "12145744_T4", "type": "Gene", "text": [ "PLP" ], "offsets": [ [ 1108, 1111 ] ], "normalized": [] }, { "id": "12145744_T5", "type": "Gene", "text": [ "DMD" ], "offsets": [ [ 1037, 1040 ] ], "normalized": [] }, { "id": "12145744_T6", "type": "Gene", "text": [ "Sec4" ], "offsets": [ [ 1218, 1222 ] ], "normalized": [] }, { "id": "12145744_T7", "type": "Gene", "text": [ "Ras" ], "offsets": [ [ 1280, 1283 ] ], "normalized": [] }, { "id": "12145744_T8", "type": "Gene", "text": [ "RLGP" ], "offsets": [ [ 1317, 1321 ] ], "normalized": [] }, { "id": "12145744_T9", "type": "Gene", "text": [ "RLGP" ], "offsets": [ [ 1352, 1356 ] ], "normalized": [] }, { "id": "12145744_T10", "type": "Gene", "text": [ "RLGP" ], "offsets": [ [ 1406, 1410 ] ], "normalized": [] }, { "id": "12145744_T2", "type": "Gene", "text": [ "DMD" ], "offsets": [ [ 563, 566 ] ], "normalized": [] }, { "id": "12145744_T1", "type": "Gene", "text": [ "Ras" ], "offsets": [ [ 50, 53 ] ], "normalized": [] } ]

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[ { "id": "12145744_R1", "type": "Equals", "arg1_id": "12145744_T3", "arg2_id": "12145744_T4", "normalized": [] } ]

[ { "id": "12428213__text", "type": "abstract", "text": [ "myotilin Mutation found in second pedigree with LGMD1A. Limb-girdle muscular dystrophy 1A (LGMD1A [MIM 159000]) is an autosomal dominant form of muscular dystrophy characterized by adult onset of proximal weakness progressing to distal muscle weakness. We have reported elsewhere a mutation in the myotilin gene in a large, North American family of German descent. Here, we report the mutation screening of an additional 86 families with a variety of neuromuscular pathologies. We have identified a new myotilin mutation in an Argentinian pedigree with LGMD1 that is predicted to result in the conversion of serine 55 to phenylalanine (S55F). This mutation has not been found in 392 control chromosomes and is located in the unique N-terminal domain of myotilin, only two residues from the T57I mutation reported elsewhere. Both T57I and S55F are located outside the alpha-actinin and gamma-filamin binding sites within myotilin. The identification of two independent pedigrees with the same disease, each bearing a different mutation in the same gene, has long been the gold standard for establishing a causal relationship between defects in a gene and the resultant disease. As a description of the second known pedigree with LGMD1A, this finding constitutes that gold standard of proof that mutations in the myotilin gene cause LGMD1A.\n" ], "offsets": [ [ 0, 1339 ] ] } ]

[ { "id": "12428213_T1", "type": "Gene", "text": [ "LGMD1A" ], "offsets": [ [ 48, 54 ] ], "normalized": [] }, { "id": "12428213_T2", "type": "Gene", "text": [ "myotilin" ], "offsets": [ [ 0, 8 ] ], "normalized": [] }, { "id": "12428213_T3", "type": "Gene", "text": [ "LGMD1A" ], "offsets": [ [ 91, 97 ] ], "normalized": [] }, { "id": "12428213_T4", "type": "Gene", "text": [ "Limb-girdle muscular dystrophy 1A" ], "offsets": [ [ 56, 89 ] ], "normalized": [] }, { "id": "12428213_T5", "type": "Gene", "text": [ "LGMD1" ], "offsets": [ [ 553, 558 ] ], "normalized": [] }, { "id": "12428213_T6", "type": "SNP", "text": [ "S55F" ], "offsets": [ [ 636, 640 ] ], "normalized": [] }, { "id": "12428213_T7", "type": "Gene", "text": [ "myotilin" ], "offsets": [ [ 753, 761 ] ], "normalized": [] }, { "id": "12428213_T8", "type": "SNP", "text": [ "T57I" ], "offsets": [ [ 790, 794 ] ], "normalized": [] }, { "id": "12428213_T9", "type": "SNP", "text": [ "T57I" ], "offsets": [ [ 829, 833 ] ], "normalized": [] }, { "id": "12428213_T10", "type": "SNP", "text": [ "S55F" ], "offsets": [ [ 838, 842 ] ], "normalized": [] }, { "id": "12428213_T11", "type": "Gene", "text": [ "myotilin" ], "offsets": [ [ 920, 928 ] ], "normalized": [] }, { "id": "12428213_T12", "type": "Gene", "text": [ "LGMD1A" ], "offsets": [ [ 1228, 1234 ] ], "normalized": [] }, { "id": "12428213_T13", "type": "Gene", "text": [ "LGMD1A" ], "offsets": [ [ 1331, 1337 ] ], "normalized": [] }, { "id": "12428213_T14", "type": "Gene", "text": [ "myotilin" ], "offsets": [ [ 1311, 1319 ] ], "normalized": [] }, { "id": "12428213_T15", "type": "SNP", "text": [ "serine 55 to phenylalanine" ], "offsets": [ [ 608, 634 ] ], "normalized": [] } ]

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[ { "id": "12428213_R1", "type": "Equals", "arg1_id": "12428213_T4", "arg2_id": "12428213_T3", "normalized": [] }, { "id": "12428213_R2", "type": "AssociatedTo", "arg1_id": "12428213_T6", "arg2_id": "12428213_T5", "normalized": [] }, { "id": "12428213_R3", "type": "AssociatedTo", "arg1_id": "12428213_T8", "arg2_id": "12428213_T7", "normalized": [] }, { "id": "12428213_R4", "type": "AssociatedTo", "arg1_id": "12428213_T10", "arg2_id": "12428213_T11", "normalized": [] }, { "id": "12428213_R5", "type": "AssociatedTo", "arg1_id": "12428213_T9", "arg2_id": "12428213_T11", "normalized": [] }, { "id": "12428213_R6", "type": "AssociatedTo", "arg1_id": "12428213_T15", "arg2_id": "12428213_T5", "normalized": [] } ]

[ { "id": "12058347__text", "type": "abstract", "text": [ "Heterozygous submicroscopic inversions involving olfactory receptor-gene clusters mediate the recurrent t(4;8)(p16;p23) translocation. The t(4;8)(p16;p23) translocation, in either the balanced form or the unbalanced form, has been reported several times. Taking into consideration the fact that this translocation may be undetected in routine cytogenetics, we find that it may be the most frequent translocation after t(11q;22q), which is the most common reciprocal translocation in humans. Case subjects with der(4) have the Wolf-Hirschhorn syndrome, whereas case subjects with der(8) show a milder spectrum of dysmorphic features. Two pairs of the many olfactory receptor (OR)-gene clusters are located close to each other, on both 4p16 and 8p23. Previously, we demonstrated that an inversion polymorphism of the OR region at 8p23 plays a crucial role in the generation of chromosomal imbalances through unusual meiotic exchanges. These findings prompted us to investigate whether OR-related inversion polymorphisms at 4p16 and 8p23 might also be involved in the origin of the t(4;8)(p16;p23) translocation. In seven case subjects (five of whom both represented de novo cases and were of maternal origin), including individuals with unbalanced and balanced translocations, we demonstrated that the breakpoints fell within the 4p and 8p OR-gene clusters. FISH experiments with appropriate bacterial-artificial-chromosome probes detected heterozygous submicroscopic inversions of both 4p and 8p regions in all the five mothers of the de novo case subjects. Heterozygous inversions on 4p16 and 8p23 were detected in 12.5% and 26% of control subjects, respectively, whereas 2.5% of them were scored as doubly heterozygous. These novel data emphasize the importance of segmental duplications and large-scale genomic polymorphisms in the evolution and pathology of the human genome.\n" ], "offsets": [ [ 0, 1879 ] ] } ]

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[ { "id": "12424708__text", "type": "abstract", "text": [ "Structural and functional characterization of factor H mutations associated with atypical hemolytic uremic syndrome. Genetic studies have demonstrated the involvement of the complement regulator factor H in nondiarrheal, nonverocytotoxin (i.e., atypical) cases of hemolytic uremic syndrome. Different factor H mutations have been identified in 10%-30% of patients with atypical hemolytic uremic syndrome (aHUS), and most of these mutations alter single amino acids in the C-terminal region of factor H. Although these mutations are considered to be responsible for the disease, the precise role that factor H plays in the pathogenesis of aHUS is unknown. We report here the structural and functional characterization of three different factor H proteins purified from the plasma of patients with aHUS who carry the factor H mutations W1183L, V1197A, or R1210C. Structural anomalies in factor H were found only in R1210C carriers; these individuals show, in their plasma, a characteristic high-molecular-weight factor H protein that results from the covalent interaction between factor H and human serum albumin. Most important, all three aHUS-associated factor H proteins have a normal cofactor activity in the proteolysis of fluid-phase C3b by factor I but show very low binding to surface-bound C3b. This functional impairment was also demonstrated in recombinant mutant factor H proteins expressed in COS7 cells. These data support the hypothesis that patients with aHUS carry a specific dysfunction in the protection of cellular surfaces from complement activation, offering new possibilities to improve diagnosis and develop appropriate therapies.\n" ], "offsets": [ [ 0, 1653 ] ] } ]

[ { "id": "12424708_T1", "type": "Gene", "text": [ "factor H" ], "offsets": [ [ 301, 309 ] ], "normalized": [] }, { "id": "12424708_T2", "type": "Gene", "text": [ "factor H" ], "offsets": [ [ 195, 203 ] ], "normalized": [] }, { "id": "12424708_T3", "type": "Gene", "text": [ "factor H" ], "offsets": [ [ 493, 501 ] ], "normalized": [] }, { "id": "12424708_T4", "type": "Gene", "text": [ "factor H" ], "offsets": [ [ 600, 608 ] ], "normalized": [] }, { "id": "12424708_T5", "type": "Gene", "text": [ "factor H" ], "offsets": [ [ 736, 744 ] ], "normalized": [] }, { "id": "12424708_T6", "type": "SNP", "text": [ "W1183L" ], "offsets": [ [ 834, 840 ] ], "normalized": [] }, { "id": "12424708_T7", "type": "SNP", "text": [ "V1197A" ], "offsets": [ [ 842, 848 ] ], "normalized": [] }, { "id": "12424708_T8", "type": "SNP", "text": [ "R1210C" ], "offsets": [ [ 853, 859 ] ], "normalized": [] }, { "id": "12424708_T9", "type": "Gene", "text": [ "factor H" ], "offsets": [ [ 815, 823 ] ], "normalized": [] }, { "id": "12424708_T10", "type": "Gene", "text": [ "factor H" ], "offsets": [ [ 885, 893 ] ], "normalized": [] }, { "id": "12424708_T11", "type": "Gene", "text": [ "factor H" ], "offsets": [ [ 1010, 1018 ] ], "normalized": [] }, { "id": "12424708_T12", "type": "Gene", "text": [ "factor H" ], "offsets": [ [ 1078, 1086 ] ], "normalized": [] }, { "id": "12424708_T13", "type": "Gene", "text": [ "factor H" ], "offsets": [ [ 1154, 1162 ] ], "normalized": [] }, { "id": "12424708_T14", "type": "Gene", "text": [ "factor H" ], "offsets": [ [ 1373, 1381 ] ], "normalized": [] }, { "id": "12424708_T15", "type": "Gene", "text": [ "factor H" ], "offsets": [ [ 46, 54 ] ], "normalized": [] }, { "id": "12424708_T16", "type": "SNP", "text": [ "R1210C" ], "offsets": [ [ 913, 919 ] ], "normalized": [] } ]

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[ { "id": "12424708_R1", "type": "AssociatedTo", "arg1_id": "12424708_T6", "arg2_id": "12424708_T9", "normalized": [] }, { "id": "12424708_R2", "type": "AssociatedTo", "arg1_id": "12424708_T7", "arg2_id": "12424708_T9", "normalized": [] }, { "id": "12424708_R3", "type": "AssociatedTo", "arg1_id": "12424708_T8", "arg2_id": "12424708_T9", "normalized": [] }, { "id": "12424708_R4", "type": "AssociatedTo", "arg1_id": "12424708_T16", "arg2_id": "12424708_T10", "normalized": [] } ]

[ { "id": "11845408__text", "type": "abstract", "text": [ "An autosomal recessive form of bilateral frontoparietal polymicrogyria maps to chromosome 16q12.2-21. Polymicrogyria is a cerebral cortical malformation that is grossly characterized by excessive cortical folding and microscopically characterized by abnormal cortical layering. Although polymicrogyria appears to have one or more genetic causes, no polymicrogyria loci have been identified. Here we describe the clinical and radiographic features of a new genetic form of polymicrogyria and localize the responsible gene. We studied two consanguineous Palestinian pedigrees with an autosomal recessive form of bilateral frontoparietal polymicrogyria (BFPP), using linkage analysis. Five affected children had moderate-to-severe mental retardation, developmental delay, and esotropia, and four of the five affected children developed seizures. Brain magnetic-resonance imaging revealed polymicrogyria that was most prominent in the frontal and parietal lobes but involved other cortical areas as well. A genomewide linkage screen revealed a single locus that was identical by descent in affected children in both families and showed a single disease-associated haplotype, suggesting a common founder mutation. The locus for BFPP maps to chromosome 16q12.2-21, with a minimal interval of 17 cM. For D16S514, the maximal pooled two-point LOD score was 3.98, and the maximal multipoint LOD score was 4.57. This study provides the first genetic evidence that BFPP is an autosomal recessive disorder and serves as a starting point for the identification of the responsible gene.\n" ], "offsets": [ [ 0, 1573 ] ] } ]

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[ { "id": "9718347__text", "type": "abstract", "text": [ "Molecular analysis of 9p deletions associated with XY sex reversal: refining the localization of a sex-determining gene to the tip of the chromosome.\n" ], "offsets": [ [ 0, 150 ] ] } ]

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[ { "id": "9497253__text", "type": "abstract", "text": [ "Splice-site mutations: a novel genetic mechanism of Crigler-Najjar syndrome type 1. Crigler-Najjar syndrome type 1 (CN-1) is a recessively inherited, potentially lethal disorder characterized by severe unconjugated hyperbilirubinemia resulting from deficiency of the hepatic enzyme bilirubin-UDP-glucuronosyltransferase. In all CN-1 patients studied, structural mutations in one of the five exons of the gene (UGT1A1) encoding the uridinediphosphoglucuronate glucuronosyltransferase (UGT) isoform bilirubin-UGT1 were implicated in the absence or inactivation of the enzyme. We report two patients in whom CN-1 is caused, instead, by mutations in the noncoding intronic region of the UGT1A1 gene. One patient (A) was homozygous for a G-->C mutation at the splice-donor site in the intron, between exon 1 and exon 2. The other patient (B) was heterozygous for an A-->G shift at the splice-acceptor site in intron 3, and in the second allele a premature translation-termination codon in exon 1 was identified. Bilirubin-UGT1 mRNA is difficult to obtain, since it is expressed in the liver only. To determine the effects of these splice-junction mutations, we amplified genomic DNA of the relevant splice junctions. The amplicons were expressed in COS-7 cells, and the expressed mRNAs were analyzed. In both cases, splice-site mutations led to the use of cryptic splice sites, with consequent deletions in the processed mRNA. This is the first report of intronic mutations causing CN-1 and of the determination of the consequences of these mutations on mRNA structure, by ex vivo expression.\n" ], "offsets": [ [ 0, 1588 ] ] } ]

[ { "id": "9497253_T1", "type": "Gene", "text": [ "(UGT1A1)" ], "offsets": [ [ 409, 417 ] ], "normalized": [] }, { "id": "9497253_T2", "type": "Gene", "text": [ "uridinediphosphoglucuronate glucuronosyltransferase" ], "offsets": [ [ 431, 482 ] ], "normalized": [] }, { "id": "9497253_T3", "type": "Gene", "text": [ "(UGT)" ], "offsets": [ [ 483, 488 ] ], "normalized": [] }, { "id": "9497253_T4", "type": "Gene", "text": [ "bilirubin-UGT1" ], "offsets": [ [ 497, 511 ] ], "normalized": [] }, { "id": "9497253_T5", "type": "Gene", "text": [ "UGT1A1" ], "offsets": [ [ 683, 689 ] ], "normalized": [] }, { "id": "9497253_T6", "type": "Gene", "text": [ "Bilirubin-UGT1" ], "offsets": [ [ 1007, 1021 ] ], "normalized": [] } ]

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[ { "id": "9634522__text", "type": "abstract", "text": [ "The 8765delAG mutation in BRCA2 is common among Jews of Yemenite extraction.\n" ], "offsets": [ [ 0, 77 ] ] } ]

[ { "id": "9634522_T1", "type": "SNP", "text": [ "8765delAG" ], "offsets": [ [ 4, 13 ] ], "normalized": [] }, { "id": "9634522_T2", "type": "Gene", "text": [ "BRCA2" ], "offsets": [ [ 26, 31 ] ], "normalized": [] } ]

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[ { "id": "9634522_R1", "type": "AssociatedTo", "arg1_id": "9634522_T1", "arg2_id": "9634522_T2", "normalized": [] } ]

[ { "id": "9792853__text", "type": "abstract", "text": [ "Development and maintenance of ear innervation and function: lessons from mutations in mouse and man.\n" ], "offsets": [ [ 0, 102 ] ] } ]

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[ { "id": "9463308__text", "type": "abstract", "text": [ "Susceptibility to relapsing-progressive multiple sclerosis is associated with inheritance of genes linked to the variable region of the TcR beta locus: use of affected family-based controls. We tested the hypothesis that susceptibility to relapsing-progressive (RP) (but not to relapsing-remitting [RR]) multiple sclerosis (MS) is associated with a gene linked to the TcR beta-chain variable region delimited by the Vbeta8-BamHI and Vbeta11-BamHI RFLP alleles in DRw15+ MS patients, using a contingency-table test of patient data and affected family-based controls. Control alleles and haplotypes were composed of parental marker alleles and haplotypes not transmitted to the affected child, in 90 simplex and 31 multiplex families from British Columbia. A total of 6,164 alleles at 11 loci were segregated through families of probands with RP MS or RR MS. The Vbeta8-Vbeta11 subhaplotype frequencies in the DRw15+ RP MS (but not RR MS) patients differed from control frequencies, because of an increase of the 2-1 subhaplotype (P=.02). Vbeta8-BamHI and Vbeta11-BamHI allele frequencies (P=.05 and .009, respectively) in the DRw15+ RP MS (but not RR MS) patients differed from control frequencies. The Vbeta1-Vbeta8 subhaplotype frequencies in the DRw15- RP MS (but not RR MS) patients differed from control frequencies (P=.03), with a significantly increased frequency of the 1-1 subhaplotype (P=.01; RR=7.1) in RP MS versus RR MS patients. Susceptibility to RP MS is associated both with a recessive inheritance of a gene linked to the 3' (Vbeta11) end of the 2-1 subhaplotype defined by the Vbeta8-BamHI and Vbeta11-BamHI alleles in DRw15+ patients and with a gene, located on the 1-1 subhaplotype, defined by the Vbeta1-TaqI and Vbeta8-MspI alleles of the TcR beta-chain complex in DRw15- patients.\n" ], "offsets": [ [ 0, 1803 ] ] } ]

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[ { "id": "9792882__text", "type": "abstract", "text": [ "Prevalence of mutations in TIGR/Myocilin in patients with adult and juvenile primary open-angle glaucoma.\n" ], "offsets": [ [ 0, 106 ] ] } ]

[ { "id": "9792882_T1", "type": "Gene", "text": [ "TIGR/Myocilin" ], "offsets": [ [ 27, 40 ] ], "normalized": [] } ]

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[ { "id": "9758627__text", "type": "abstract", "text": [ "A missense mutation in the zinc-finger domain of the human hairless gene underlies congenital atrichia in a family of Irish travellers. Congenital atrichia is a rare, recessively inherited form of hair loss affecting both males and females and is characterized by a complete absence of hair follicles. Recently, a mutation in the human hairless gene was implicated in the pathogenesis of congenital atrichia. The human hairless gene encodes a putative single zinc-finger transcription-factor protein with restricted expression in brain and skin, which is believed to regulate catagen remodeling in the hair cycle. In this study, we report the identification of a missense mutation in the zinc-finger domain of the hairless gene in a large inbred family of Irish Travellers with congenital atrichia. The mutated arginine residue is conserved among human, mouse, and rat, suggesting that it is of significant importance to the function of the zinc-finger domain.\n" ], "offsets": [ [ 0, 961 ] ] } ]

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[ { "id": "9497255__text", "type": "abstract", "text": [ "Autosomal genomic scan for loci linked to obesity and energy metabolism in Pima Indians. An autosomal genomic scan to search for linkage to obesity and energy metabolism was completed in Pima Indians, a population prone to obesity. Obesity was assessed by percent body fat (by hydrodensitometry) and fat distribution (the ratio of waist circumference to thigh circumference). Energy metabolism was measured in a respiratory chamber as 24-h metabolic rate, sleeping metabolic rate, and 24-h respiratory quotient (24RQ), an indicator of the ratio of carbohydrate oxidation to fat oxidation. Five hundred sixteen microsatellite markers with a median spacing of 6.4 cM were analyzed, in 362 siblings who had measurements of body composition and in 220 siblings who had measurements of energy metabolism. These comprised 451 sib pairs in 127 nuclear families, for linkage analysis to obesity, and 236 sib pairs in 82 nuclear families, for linkage analysis to energy metabolism. Pointwise and multipoint methods for regression of sib-pair differences in identity by descent, as well as a sibling-based variance-components method, were used to detect linkage. LOD scores >=2 were found at 11q21-q22, for percent body fat (LOD=2.1; P=.001), at 11q23-q24, for 24-h energy expenditure (LOD=2.0; P=.001), and at 1p31-p21 (LOD=2.0) and 20q11.2 (LOD=3.0; P=.0001), for 24RQ, by pointwise and multipoint analyses. With the variance-components method, the highest LOD score (LOD=2.3 P=.0006) was found at 18q21, for percent body fat, and at 1p31-p21 (LOD=2.8; P=.0003), for 24RQ. Possible candidate genes include LEPR (leptin receptor), at 1p31, and ASIP (agouti-signaling protein), at 20q11.2.\n" ], "offsets": [ [ 0, 1680 ] ] } ]

[ { "id": "9497255_T1", "type": "Gene", "text": [ "LEPR" ], "offsets": [ [ 1598, 1602 ] ], "normalized": [] }, { "id": "9497255_T2", "type": "Gene", "text": [ "(leptin receptor)," ], "offsets": [ [ 1603, 1621 ] ], "normalized": [] }, { "id": "9497255_T3", "type": "Gene", "text": [ "ASIP" ], "offsets": [ [ 1635, 1639 ] ], "normalized": [] }, { "id": "9497255_T4", "type": "Gene", "text": [ "(agouti-signaling protein)," ], "offsets": [ [ 1640, 1667 ] ], "normalized": [] } ]

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[ { "id": "9497255_R1", "type": "Equals", "arg1_id": "9497255_T1", "arg2_id": "9497255_T2", "normalized": [] }, { "id": "9497255_R2", "type": "Equals", "arg1_id": "9497255_T3", "arg2_id": "9497255_T4", "normalized": [] } ]

[ { "id": "9838272__text", "type": "abstract", "text": [ "The sib transmission/disequilibrium test is a Mantel-Haenszel test.\n" ], "offsets": [ [ 0, 68 ] ] } ]

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[ { "id": "9443866__text", "type": "abstract", "text": [ "Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations. To facilitate the evaluation of ATM heterozygotes for susceptibility to other diseases, such as breast cancer, we have attempted to define the most common mutations and their frequencies in ataxia-telangiectasia (A-T) homozygotes from 10 ethnic populations. Both genomic mutations and their effects on cDNA were characterized. Protein-truncation testing of the entire ATM cDNA detected 92 (66%) truncating mutations in 140 mutant alleles screened. The haplotyping of patients with identical mutations indicates that almost all of these represent common ancestry and that very few spontaneously recurring ATM mutations exist. Assays requiring minimal amounts of genomic DNA were designed to allow rapid screening for common ethnic mutations. These rapid assays detected mutations in 76% of Costa Rican patients (3), 50% of Norwegian patients (1), 25% of Polish patients (4), and 14% of Italian patients (1), as well as in patients of Amish/Mennonite and Irish English backgrounds. Additional mutations were observed in Japanese, Utah Mormon, and African American patients. These assays should facilitate screening for A-T heterozygotes in the populations studied.\n" ], "offsets": [ [ 0, 1282 ] ] } ]

[ { "id": "9443866_T1", "type": "Gene", "text": [ "ATM" ], "offsets": [ [ 87, 90 ] ], "normalized": [] }, { "id": "9443866_T2", "type": "Gene", "text": [ "ATM" ], "offsets": [ [ 151, 154 ] ], "normalized": [] }, { "id": "9443866_T3", "type": "Gene", "text": [ "ATM" ], "offsets": [ [ 487, 490 ] ], "normalized": [] }, { "id": "9443866_T4", "type": "Gene", "text": [ "ATM" ], "offsets": [ [ 723, 726 ] ], "normalized": [] } ]

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[ { "id": "9718346__text", "type": "abstract", "text": [ "A gene involved in XY sex reversal is located on chromosome 9, distal to marker D9S1779. The genetic mechanisms involved in sex differentiation are poorly understood, and progress in identification of the genes involved has been slow. The fortuitous finding of chromosomal rearrangements in association with a sex-reversed phenotype has led to the isolation of SRY and SOX9, both shown to be involved in the sex-determining pathway. In addition, duplications of the X chromosome, deletions of chromosomes 9 and 10, and translocations involving chromosome 17 have been reported to be associated with abnormal testicular differentiation, leading to male-to-female sex reversal in 46,XY individuals. We present the cytogenetic and molecular analyses of four sex-reversed XY females, each with gonadal dysgenesis and other variable malformations, and with terminal deletions of distal chromosome 9p, resulting from unbalanced autosomal translocations. PCR amplification and DNA sequence analysis of SRY revealed no mutations in the high-mobility-group domain (i.e., HMG box) in any of the four patients. Conventional and molecular cytogenetic analyses of metaphase chromosomes from each patient suggest that the smallest region of overlap (SRO) of deletions involves a very small region of distal band 9p24. Loss-of-heterozygosity studies using 17 highly polymorphic microsatellite markers, as well as FISH using YAC clones corresponding to the most distal markers on 9p, showed that the SRO lies distal to marker D9S1779. These results significantly narrow the putative sex-determining gene to the very terminal region of the short arm of chromosome 9.\n" ], "offsets": [ [ 0, 1650 ] ] } ]

[ { "id": "9718346_T1", "type": "Gene", "text": [ "SRY" ], "offsets": [ [ 361, 364 ] ], "normalized": [] }, { "id": "9718346_T2", "type": "Gene", "text": [ "SOX9," ], "offsets": [ [ 369, 374 ] ], "normalized": [] }, { "id": "9718346_T3", "type": "Gene", "text": [ "SRY" ], "offsets": [ [ 995, 998 ] ], "normalized": [] } ]

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[ { "id": "9718360__text", "type": "abstract", "text": [ "\"Well-bear and well-rear\" in China?\n" ], "offsets": [ [ 0, 36 ] ] } ]

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[ { "id": "9683585__text", "type": "abstract", "text": [ "Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders. Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome predisposing to tumors of the parathyroid, endocrine pancreas, anterior pituitary, adrenal glands, and diffuse neuroendocrine tissues. The MEN1 gene has been assigned, by linkage analysis and loss of heterozygosity, to chromosome 11q13 and recently has been identified by positional cloning. In this study, a total of 84 families and/or isolated patients with either MEN1 or MEN1-related inherited endocrine tumors were screened for MEN1 germ-line mutations, by heteroduplex and sequence analysis of the MEN1 gene-coding region and untranslated exon 1. Germ-line MEN1 alterations were identified in 47/54 (87%) MEN1 families, in 9/11 (82%) isolated MEN1 patients, and in only 6/19 (31.5%) atypical MEN1-related inherited cases. We characterized 52 distinct mutations in a total of 62 MEN1 germ-line alterations. Thirty-five of the 52 mutations were frameshifts and nonsense mutations predicted to encode for a truncated MEN1 protein. We identified eight missense mutations and five in-frame deletions over the entire coding sequence. Six mutations were observed more than once in familial MEN1. Haplotype analysis in families with identical mutations indicate that these occurrences reflected mainly independent mutational events. No MEN1 germ-line mutations were found in 7/54 (13%) MEN1 families, in 2/11 (18%) isolated MEN1 cases, in 13/19 (68. 5%) MEN1-related cases, and in a kindred with familial isolated hyperparathyroidism. Two hundred twenty gene carriers (167 affected and 53 unaffected) were identified. No evidence of genotype-phenotype correlation was found. Age-related penetrance was estimated to be >95% at age >30 years. Our results add to the diversity of MEN1 germ-line mutations and provide new tools in genetic screening of MEN1 and clinically related cases.\n" ], "offsets": [ [ 0, 1962 ] ] } ]

[ { "id": "9683585_T1", "type": "Gene", "text": [ "MEN1" ], "offsets": [ [ 320, 324 ] ], "normalized": [] }, { "id": "9683585_T2", "type": "Gene", "text": [ "MEN1" ], "offsets": [ [ 548, 552 ] ], "normalized": [] }, { "id": "9683585_T3", "type": "Gene", "text": [ "MEN1" ], "offsets": [ [ 685, 689 ] ], "normalized": [] }, { "id": "9683585_T4", "type": "Gene", "text": [ "MEN1" ], "offsets": [ [ 744, 748 ] ], "normalized": [] }, { "id": "9683585_T5", "type": "Gene", "text": [ "MEN1" ], "offsets": [ [ 792, 796 ] ], "normalized": [] }, { "id": "9683585_T6", "type": "Gene", "text": [ "MEN1" ], "offsets": [ [ 830, 834 ] ], "normalized": [] }, { "id": "9683585_T7", "type": "Gene", "text": [ "MEN1" ], "offsets": [ [ 965, 969 ] ], "normalized": [] }, { "id": "9683585_T8", "type": "Gene", "text": [ "MEN1" ], "offsets": [ [ 1101, 1105 ] ], "normalized": [] }, { "id": "9683585_T9", "type": "Gene", "text": [ "MEN1." ], "offsets": [ [ 1270, 1275 ] ], "normalized": [] }, { "id": "9683585_T10", "type": "Gene", "text": [ "MEN1" ], "offsets": [ [ 1415, 1419 ] ], "normalized": [] }, { "id": "9683585_T11", "type": "Gene", "text": [ "MEN1" ], "offsets": [ [ 1465, 1469 ] ], "normalized": [] }, { "id": "9683585_T12", "type": "Gene", "text": [ "MEN1" ], "offsets": [ [ 1503, 1507 ] ], "normalized": [] }, { "id": "9683585_T13", "type": "Gene", "text": [ "MEN1" ], "offsets": [ [ 1856, 1860 ] ], "normalized": [] }, { "id": "9683585_T14", "type": "Gene", "text": [ "MEN1" ], "offsets": [ [ 1927, 1931 ] ], "normalized": [] } ]

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[ { "id": "9837829__text", "type": "abstract", "text": [ "Evidence for a Turner syndrome locus or loci at Xp11.2-p22.1. Turner syndrome is the complex human phenotype associated with complete or partial monosomy X. Principle features of Turner syndrome include short stature, ovarian failure, and a variety of other anatomic and physiological abnormalities, such as webbed neck, lymphedema, cardiovascular and renal anomalies, hypertension, and autoimmune thyroid disease. We studied 28 apparently nonmosaic subjects with partial deletions of Xp, in order to map loci responsible for various components of the Turner syndrome phenotype. Subjects were carefully evaluated for the presence or absence of Turner syndrome features, and their deletions were mapped by FISH with a panel of Xp markers. Using a statistical method to examine genotype/phenotype correlations, we mapped one or more Turner syndrome traits to a critical region in Xp11.2-p22.1. These traits included short stature, ovarian failure, high-arched palate, and autoimmune thyroid disease. The results are useful for genetic counseling of individuals with partial monosomy X. Study of additional subjects should refine the localization of Turner syndrome loci and provide a rational basis for exploration of candidate genes.\n" ], "offsets": [ [ 0, 1233 ] ] } ]

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[ { "id": "9497249__text", "type": "abstract", "text": [ "Assignment of the tibial muscular dystrophy locus to chromosome 2q31. Tibial muscular dystrophy (TMD) is a rare autosomal dominant distal myopathy with late adult onset. The phenotype is relatively mild: muscle weakness manifests in the patient's early 40s and remains confined to the tibial anterior muscles. Histopathological changes in muscle are compatible with muscular dystrophy, with the exception that rimmed vacuoles are a rather common finding. We performed a genomewide scan, with 279 highly polymorphic Cooperative Human Linkage Center microsatellite markers, on 11 affected individuals of one Finnish TMD family. The only evidence for linkage emerged from markers in a 43-cM region on chromosome 2q. In further linkage analyses, which included three other Finnish TMD families and which used a denser set of markers, a maximum two-point LOD score of 10.14 (recombination fraction of .05) was obtained with marker D2S364. Multipoint likelihood calculations, combined with the haplotype and recombination analyses, restricted the TMD locus to an approximately 1-cM critical chromosomal region without any evidence of heterogeneity. Since all the affecteds share one core haplotype, the dominance of one ancestor mutation is obvious in the Finnish TMD families. The disease locus that was found represents a novel muscular dystrophy locus, providing evidence for the involvement of one additional gene in the distal myopathy group of muscle disorders.\n" ], "offsets": [ [ 0, 1462 ] ] } ]

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[ { "id": "9718357__text", "type": "abstract", "text": [ "NTBC and alkaptonuria.\n" ], "offsets": [ [ 0, 23 ] ] } ]

[ { "id": "9718357_T1", "type": "Gene", "text": [ "NTBC" ], "offsets": [ [ 0, 4 ] ], "normalized": [] } ]

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[ { "id": "9683604__text", "type": "abstract", "text": [ "From amplification to gene in thyroid cancer: a high-resolution mapped bacterial-artificial-chromosome resource for cancer chromosome aberrations guides gene discovery after comparative genome hybridization. Chromosome rearrangements associated with neoplasms provide a rich resource for definition of the pathways of tumorigenesis. The power of comparative genome hybridization (CGH) to identify novel genes depends on the existence of suitable markers, which are lacking throughout most of the genome. We now report a general approach that translates CGH data into higher-resolution genomic-clone data that are then used to define the genes located in aneuploid regions. We used CGH to study 33 thyroid-tumor DNAs and two tumor-cell-line DNAs. The results revealed amplifications of chromosome band 2p21, with less-intense amplification on 2p13, 19q13.1, and 1p36 and with least-intense amplification on 1p34, 1q42, 5q31, 5q33-34, 9q32-34, and 14q32. To define the 2p21 region amplified, a dense array of 373 FISH-mapped chromosome 2 bacterial artificial chromosomes (BACs) was constructed, and 87 of these were hybridized to a tumor-cell line. Four BACs carried genomic DNA that was amplified in these cells. The maximum amplified region was narrowed to 3-6 Mb by multicolor FISH with the flanking BACs, and the minimum amplicon size was defined by a contig of 420 kb. Sequence analysis of the amplified BAC 1D9 revealed a fragment of the gene, encoding protein kinase C epsilon (PKCepsilon), that was then shown to be amplified and rearranged in tumor cells. In summary, CGH combined with a dense mapped resource of BACs and large-scale sequencing has led directly to the definition of PKCepsilon as a previously unmapped candidate gene involved in thyroid tumorigenesis.\n" ], "offsets": [ [ 0, 1776 ] ] } ]

[ { "id": "9683604_T1", "type": "Gene", "text": [ "protein kinase C epsilon" ], "offsets": [ [ 1457, 1481 ] ], "normalized": [] }, { "id": "9683604_T2", "type": "Gene", "text": [ "(PKCepsilon)," ], "offsets": [ [ 1482, 1495 ] ], "normalized": [] }, { "id": "9683604_T3", "type": "Gene", "text": [ "PKCepsilon" ], "offsets": [ [ 1690, 1700 ] ], "normalized": [] } ]

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[ { "id": "9683604_R1", "type": "Equals", "arg1_id": "9683604_T1", "arg2_id": "9683604_T2", "normalized": [] } ]

[ { "id": "9463309__text", "type": "abstract", "text": [ "The haptoglobin-gene deletion responsible for anhaptoglobinemia. We have found an allelic deletion of the haptoglobin (Hp) gene from an individual with anhaptoglobinemia. The Hp gene cluster consists of coding regions of the alpha chain and beta chain of the haptoglobin gene (Hp) and of the alpha chain and beta chain of the haptoglobin-related gene (Hpr), in tandem from the 5' side. Southern blot and PCR analyses have indicated that the individual with anhaptoglobinemia was homozygous for the gene deletion and that the gene deletion was included at least from the promoter region of Hp to Hpr alpha but not to Hpr beta (Hpdel). In addition, we found seven individuals with hypohaptoglobinemia in three families, and the genotypes of six of the seven individuals were found to be Hp2/Hpdel. The phenotypes and genotypes in one of these three families showed the father to be hypohaptoglobinemic (Hp2) and Hp2/Hpdel, the mother to be Hp2-1 and Hp1/Hp2, one of the two children to be hypohaptoglobinemic (Hp2) and Hp2/Hpdel, and the other child to be Hp1 and Hp1/Hpdel, showing an anomalous inheritance of Hp phenotypes in the child with Hp1. The Hp2/Hpdel individuals had an extremely low level of Hp (mean+/-SD = 0.049+/-0. 043 mg/ml; n=6), compared with the level (1.64+/-1.07 mg/ml) obtained from 52 healthy volunteers having phenotype Hp2, whereas the serum Hp level of an individual with Hp1/Hpdel was 0.50 mg/ml, which was approximately half the level of Hp in control sera from the Hp1 phenotype (1.26+/-0.33 mg/ml; n=9), showing a gene-dosage effect. The other allele (Hp2) of individuals with Hp2/Hpdel was found to have, in all exons, no mutation, by DNA sequencing. On the basis of the present study, the mechanism of anhaptoglobinemia and the mechanism of anomalous inheritance of Hp phenotypes were well explained. However, the mechanism of hypohaptoglobinemia remains unknown.\n" ], "offsets": [ [ 0, 1895 ] ] } ]

[ { "id": "9463309_T1", "type": "Gene", "text": [ "haptoglobin" ], "offsets": [ [ 106, 117 ] ], "normalized": [] }, { "id": "9463309_T2", "type": "Gene", "text": [ "(Hp)" ], "offsets": [ [ 118, 122 ] ], "normalized": [] }, { "id": "9463309_T3", "type": "Gene", "text": [ "haptoglobin" ], "offsets": [ [ 259, 270 ] ], "normalized": [] }, { "id": "9463309_T4", "type": "Gene", "text": [ "(Hp)" ], "offsets": [ [ 276, 280 ] ], "normalized": [] }, { "id": "9463309_T5", "type": "Gene", "text": [ "haptoglobin-related gene" ], "offsets": [ [ 326, 350 ] ], "normalized": [] }, { "id": "9463309_T6", "type": "Gene", "text": [ "(Hpr)," ], "offsets": [ [ 351, 357 ] ], "normalized": [] }, { "id": "9463309_T7", "type": "Gene", "text": [ "Hpr alpha" ], "offsets": [ [ 595, 604 ] ], "normalized": [] }, { "id": "9463309_T8", "type": "Gene", "text": [ "Hpr beta" ], "offsets": [ [ 616, 624 ] ], "normalized": [] }, { "id": "9463309_T9", "type": "Gene", "text": [ "(Hp2)" ], "offsets": [ [ 900, 905 ] ], "normalized": [] }, { "id": "9463309_T10", "type": "Gene", "text": [ "Hp2-1" ], "offsets": [ [ 938, 943 ] ], "normalized": [] }, { "id": "9463309_T11", "type": "Gene", "text": [ "(Hp2)" ], "offsets": [ [ 1007, 1012 ] ], "normalized": [] }, { "id": "9463309_T12", "type": "Gene", "text": [ "Hp1" ], "offsets": [ [ 1054, 1057 ] ], "normalized": [] }, { "id": "9463309_T13", "type": "Gene", "text": [ "Hp1." ], "offsets": [ [ 1141, 1145 ] ], "normalized": [] }, { "id": "9463309_T14", "type": "Gene", "text": [ "Hp2," ], "offsets": [ [ 1343, 1347 ] ], "normalized": [] }, { "id": "9463309_T15", "type": "Gene", "text": [ "Hp1" ], "offsets": [ [ 1493, 1496 ] ], "normalized": [] }, { "id": "9463309_T16", "type": "Gene", "text": [ "(Hp2)" ], "offsets": [ [ 1580, 1585 ] ], "normalized": [] } ]

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[ { "id": "9463309_R1", "type": "Equals", "arg1_id": "9463309_T1", "arg2_id": "9463309_T2", "normalized": [] }, { "id": "9463309_R2", "type": "Equals", "arg1_id": "9463309_T3", "arg2_id": "9463309_T4", "normalized": [] }, { "id": "9463309_R3", "type": "Equals", "arg1_id": "9463309_T5", "arg2_id": "9463309_T6", "normalized": [] } ]

[ { "id": "9545410__text", "type": "abstract", "text": [ "A gene for familial juvenile polyposis maps to chromosome 18q21.1. Familial juvenile polyposis (FJP) is a hamartomatouspolyposis syndrome in which affected family members develop upper and lower gastrointestinal juvenile polyps and are at increased risk for gastrointestinal cancer. A genetic locus for FJP has not yet been identified by linkage; therefore, the objective of this study was to perform a focused genome screen in a large family segregating FJP. No evidence for linkage was found with markers near MSH2, MLH1, MCC, APC, HMPS, CDKN2A, JP1, PTEN, KRAS2, TP53, or LKB1. Linkage to FJP was established with several markers from chromosome 18q21.1. The maximum LOD score was 5.00, with marker D18S1099 (recombination fraction of .001). Analysis of critical recombinants places the FJP gene in an 11.9-cM interval bounded by D18S1118 and D18S487, a region that also contains the tumor-suppressor genes DCC and DPC4. These data demonstrate localization of a gene for FJP to chromosome 18q21.1 by linkage, and they raise the possibility that either DCC or DPC4 could be responsible for FJP.\n" ], "offsets": [ [ 0, 1097 ] ] } ]

[ { "id": "9545410_T1", "type": "Gene", "text": [ "MSH2," ], "offsets": [ [ 512, 517 ] ], "normalized": [] }, { "id": "9545410_T2", "type": "Gene", "text": [ "MLH1," ], "offsets": [ [ 518, 523 ] ], "normalized": [] }, { "id": "9545410_T3", "type": "Gene", "text": [ "MCC," ], "offsets": [ [ 524, 528 ] ], "normalized": [] }, { "id": "9545410_T4", "type": "Gene", "text": [ "APC," ], "offsets": [ [ 529, 533 ] ], "normalized": [] }, { "id": "9545410_T5", "type": "Gene", "text": [ "HMPS," ], "offsets": [ [ 534, 539 ] ], "normalized": [] }, { "id": "9545410_T6", "type": "Gene", "text": [ "CDKN2A," ], "offsets": [ [ 540, 547 ] ], "normalized": [] }, { "id": "9545410_T7", "type": "Gene", "text": [ "JP1," ], "offsets": [ [ 548, 552 ] ], "normalized": [] }, { "id": "9545410_T8", "type": "Gene", "text": [ "PTEN," ], "offsets": [ [ 553, 558 ] ], "normalized": [] }, { "id": "9545410_T9", "type": "Gene", "text": [ "KRAS2," ], "offsets": [ [ 559, 565 ] ], "normalized": [] }, { "id": "9545410_T10", "type": "Gene", "text": [ "TP53," ], "offsets": [ [ 566, 571 ] ], "normalized": [] }, { "id": "9545410_T11", "type": "Gene", "text": [ "LKB1." ], "offsets": [ [ 575, 580 ] ], "normalized": [] }, { "id": "9545410_T12", "type": "Gene", "text": [ "DCC" ], "offsets": [ [ 910, 913 ] ], "normalized": [] }, { "id": "9545410_T13", "type": "Gene", "text": [ "DPC4." ], "offsets": [ [ 918, 923 ] ], "normalized": [] }, { "id": "9545410_T14", "type": "Gene", "text": [ "DCC" ], "offsets": [ [ 1055, 1058 ] ], "normalized": [] }, { "id": "9545410_T15", "type": "Gene", "text": [ "DPC4" ], "offsets": [ [ 1062, 1066 ] ], "normalized": [] } ]

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[ { "id": "9837820__text", "type": "abstract", "text": [ "A common and recurrent 13-bp deletion in the autoimmune regulator gene in British kindreds with autoimmune polyendocrinopathy type 1. Autoimmune polyendocrinopathy type 1 (APS1) is an autosomal recessive disorder characterized by autoimmune hypoparathyroidism, autoimmune adrenocortical failure, and mucocutaneous candidiasis. Recently, an autoimmune regulator gene (AIRE-1), which is located on chromosome 21q22.3, has been identified, and mutations in European kindreds with APS1 have been described. We used SSCP analysis and direct DNA sequencing to screen the entire 1,635-bp coding region of AIRE-1 in 12 British families with APS1. A 13-bp deletion (964del13) was found to account for 17 of the 24 possible mutant AIRE-1 alleles, in our kindreds. This mutation was found to occur de novo in one affected subject. A common haplotype spanning the AIRE-1 locus was found in chromosomes that carried the 964del13 mutation, suggesting a founder effect in our population. One of 576 normal subjects was also a heterozygous carrier of the 964del13 mutation. Six other point mutations were found in AIRE-1, including two 1-bp deletions, three missense mutations (R15L, L28P, and Y90C), and a nonsense mutation (R257*). The high frequency of the 964del13 allele and the clustering of the other AIRE-1 mutations may allow rapid molecular screening for APS1 in British kindreds. Furthermore, the prevalence of the 964del13 AIRE-1 mutation may have implications in the pathogenesis of the more common autoimmune endocrinopathies in our population.\n" ], "offsets": [ [ 0, 1543 ] ] } ]

[ { "id": "9837820_T1", "type": "Gene", "text": [ "(AIRE-1)," ], "offsets": [ [ 366, 375 ] ], "normalized": [] }, { "id": "9837820_T2", "type": "Gene", "text": [ "AIRE-1" ], "offsets": [ [ 598, 604 ] ], "normalized": [] }, { "id": "9837820_T4", "type": "Gene", "text": [ "AIRE-1" ], "offsets": [ [ 721, 727 ] ], "normalized": [] }, { "id": "9837820_T5", "type": "Gene", "text": [ "AIRE-1" ], "offsets": [ [ 852, 858 ] ], "normalized": [] }, { "id": "9837820_T6", "type": "SNP", "text": [ "964del13" ], "offsets": [ [ 907, 915 ] ], "normalized": [] }, { "id": "9837820_T7", "type": "SNP", "text": [ "964del13" ], "offsets": [ [ 1039, 1047 ] ], "normalized": [] }, { "id": "9837820_T8", "type": "Gene", "text": [ "AIRE-1," ], "offsets": [ [ 1098, 1105 ] ], "normalized": [] }, { "id": "9837820_T13", "type": "SNP", "text": [ "964del13" ], "offsets": [ [ 1244, 1252 ] ], "normalized": [] }, { "id": "9837820_T14", "type": "Gene", "text": [ "AIRE-1" ], "offsets": [ [ 1292, 1298 ] ], "normalized": [] }, { "id": "9837820_T15", "type": "SNP", "text": [ "964del13" ], "offsets": [ [ 1410, 1418 ] ], "normalized": [] }, { "id": "9837820_T16", "type": "Gene", "text": [ "AIRE-1" ], "offsets": [ [ 1419, 1425 ] ], "normalized": [] }, { "id": "9837820_T3", "type": "SNP", "text": [ "964del13" ], "offsets": [ [ 657, 665 ] ], "normalized": [] }, { "id": "9837820_T9", "type": "SNP", "text": [ "R15L" ], "offsets": [ [ 1162, 1166 ] ], "normalized": [] }, { "id": "9837820_T10", "type": "SNP", "text": [ "L28P" ], "offsets": [ [ 1168, 1172 ] ], "normalized": [] }, { "id": "9837820_T11", "type": "SNP", "text": [ "Y90C" ], "offsets": [ [ 1178, 1182 ] ], "normalized": [] }, { "id": "9837820_T12", "type": "SNP", "text": [ "R257*" ], "offsets": [ [ 1210, 1215 ] ], "normalized": [] } ]

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[ { "id": "9837820_R2", "type": "AssociatedTo", "arg1_id": "9837820_T6", "arg2_id": "9837820_T5", "normalized": [] }, { "id": "9837820_R1", "type": "AssociatedTo", "arg1_id": "9837820_T3", "arg2_id": "9837820_T4", "normalized": [] }, { "id": "9837820_R3", "type": "AssociatedTo", "arg1_id": "9837820_T9", "arg2_id": "9837820_T8", "normalized": [] }, { "id": "9837820_R4", "type": "AssociatedTo", "arg1_id": "9837820_T10", "arg2_id": "9837820_T8", "normalized": [] }, { "id": "9837820_R5", "type": "AssociatedTo", "arg1_id": "9837820_T11", "arg2_id": "9837820_T8", "normalized": [] }, { "id": "9837820_R6", "type": "AssociatedTo", "arg1_id": "9837820_T12", "arg2_id": "9837820_T8", "normalized": [] } ]

[ { "id": "11577372__text", "type": "abstract", "text": [ "Alpha-B crystallin gene (CRYAB) mutation causes dominant congenital posterior polar cataract in humans. Congenital cataracts are an important cause of bilateral visual impairment in infants. In a four-generation family of English descent, we mapped dominant congenital posterior polar cataract to chromosome 11q22-q22.3. The maximum LOD score, 3.92 at recombination fraction 0, was obtained for marker D11S898, near the gene that encodes crystallin alpha-B protein (CRYAB). By sequencing the coding regions of CRYAB, we found in exon 3 a deletion mutation, 450delA, that is associated with cataract in this family. The mutation resulted in a frameshift in codon 150 and produced an aberrant protein consisting of 184 residues. This is the first report of a mutation, in this gene, resulting in isolated congenital cataract.\n" ], "offsets": [ [ 0, 824 ] ] } ]

[ { "id": "11577372_T1", "type": "Gene", "text": [ "Alpha-B crystallin gene" ], "offsets": [ [ 0, 23 ] ], "normalized": [] }, { "id": "11577372_T2", "type": "Gene", "text": [ "CRYAB" ], "offsets": [ [ 25, 30 ] ], "normalized": [] }, { "id": "11577372_T3", "type": "Gene", "text": [ "CRYAB" ], "offsets": [ [ 466, 471 ] ], "normalized": [] }, { "id": "11577372_T4", "type": "Gene", "text": [ "CRYAB" ], "offsets": [ [ 510, 515 ] ], "normalized": [] }, { "id": "11577372_T5", "type": "SNP", "text": [ "450delA" ], "offsets": [ [ 557, 564 ] ], "normalized": [] } ]

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[ { "id": "11577372_R1", "type": "Equals", "arg1_id": "11577372_T1", "arg2_id": "11577372_T2", "normalized": [] }, { "id": "11577372_R2", "type": "AssociatedTo", "arg1_id": "11577372_T5", "arg2_id": "11577372_T4", "normalized": [] } ]

[ { "id": "11112662__text", "type": "abstract", "text": [ "A narrow segment of maternal uniparental disomy of chromosome 7q31-qter in Silver-Russell syndrome delimits a candidate gene region. Maternal uniparental disomy of chromosome 7 (matUPD7), the inheritance of both chromosomes from only the mother, is observed in approximately 10% of patients with Silver-Russell syndrome (SRS). It has been suggested that at least one imprinted gene that regulates growth and development resides on human chromosome 7. To date, three imprinted genes-PEG1/MEST, gamma2-COP, and GRB10-have been identified on chromosome 7, but their role in the etiology of SRS remains uncertain. In a systematic screening with microsatellite markers, for matUPD7 cases among patients with SRS, we identified a patient who had a small segment of matUPD7 and biparental inheritance of the remainder of chromosome 7. Such a pattern may be explained by somatic recombination in the zygote. The matUPD7 segment at 7q31-qter extends for 35 Mb and includes the imprinted gene cluster of PEG1/MEST and gamma2-COP at 7q32. GRB10 at 7p11.2-p12 is located within a region of biparental inheritance. Although partial UPD has previously been reported for chromosomes 6, 11, 14, and 15, this is the first report of a patient with SRS who has segmental matUPD7. Our findings delimit a candidate imprinted region sufficient to cause SRS.\n" ], "offsets": [ [ 0, 1336 ] ] } ]

[ { "id": "11112662_T1", "type": "Gene", "text": [ "PEG1" ], "offsets": [ [ 482, 486 ] ], "normalized": [] }, { "id": "11112662_T2", "type": "Gene", "text": [ "gamma2-COP," ], "offsets": [ [ 493, 504 ] ], "normalized": [] }, { "id": "11112662_T3", "type": "Gene", "text": [ "GRB10" ], "offsets": [ [ 509, 514 ] ], "normalized": [] }, { "id": "11112662_T4", "type": "Gene", "text": [ "PEG1" ], "offsets": [ [ 994, 998 ] ], "normalized": [] }, { "id": "11112662_T5", "type": "Gene", "text": [ "gamma2-COP" ], "offsets": [ [ 1008, 1018 ] ], "normalized": [] }, { "id": "11112662_T6", "type": "Gene", "text": [ "GRB10" ], "offsets": [ [ 1028, 1033 ] ], "normalized": [] }, { "id": "11112662_T7", "type": "Gene", "text": [ "MEST" ], "offsets": [ [ 487, 491 ] ], "normalized": [] }, { "id": "11112662_T8", "type": "Gene", "text": [ "MEST" ], "offsets": [ [ 999, 1003 ] ], "normalized": [] } ]

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[ { "id": "11359216__text", "type": "abstract", "text": [ "Mitochondria and the quality of human gametes.\n" ], "offsets": [ [ 0, 47 ] ] } ]

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[ { "id": "11462173__text", "type": "abstract", "text": [ "p63 Gene mutations in eec syndrome, limb-mammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation. p63 mutations have been associated with EEC syndrome (ectrodactyly, ectodermal dysplasia, and cleft lip/palate), as well as with nonsyndromic split hand-split foot malformation (SHFM). We performed p63 mutation analysis in a sample of 43 individuals and families affected with EEC syndrome, in 35 individuals affected with SHFM, and in three families with the EEC-like condition limb-mammary syndrome (LMS), which is characterized by ectrodactyly, cleft palate, and mammary-gland abnormalities. The results differed for these three conditions. p63 gene mutations were detected in almost all (40/43) individuals affected with EEC syndrome. Apart from a frameshift mutation in exon 13, all other EEC mutations were missense, predominantly involving codons 204, 227, 279, 280, and 304. In contrast, p63 mutations were detected in only a small proportion (4/35) of patients with isolated SHFM. p63 mutations in SHFM included three novel mutations: a missense mutation (K193E), a nonsense mutation (Q634X), and a mutation in the 3' splice site for exon 5. The fourth SHFM mutation (R280H) in this series was also found in a patient with classical EEC syndrome, suggesting partial overlap between the EEC and SHFM mutational spectra. The original family with LMS (van Bokhoven et al. 1999) had no detectable p63 mutation, although it clearly localizes to the p63 locus in 3q27. In two other small kindreds affected with LMS, frameshift mutations were detected in exons 13 and 14, respectively. The combined data show that p63 is the major gene for EEC syndrome, and that it makes a modest contribution to SHFM. There appears to be a genotype-phenotype correlation, in that there is a specific pattern of missense mutations in EEC syndrome that are not generally found in SHFM or LMS.\n" ], "offsets": [ [ 0, 1927 ] ] } ]

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[ { "id": "11156534__text", "type": "abstract", "text": [ "A novel syndrome affecting multiple mitochondrial functions, located by microcell-mediated transfer to chromosome 2p14-2p13. We have studied cultured skin fibroblasts from three siblings and one unrelated individual, all of whom had fatal mitochondrial disease manifesting soon after birth. After incubation with 1 mM glucose, these four cell strains exhibited lactate/pyruvate ratios that were six times greater than those of controls. On further analysis, enzymatic activities of the pyruvate dehydrogenase complex, the 2-oxoglutarate dehydrogenase complex, NADH cytochrome c reductase, succinate dehydrogenase, and succinate cytochrome c reductase were severely deficient. In two of the siblings the enzymatic activity of cytochrome oxidase was mildly decreased (by approximately 50%). Metabolite analysis performed on urine samples taken from these patients revealed high levels of glycine, leucine, valine, and isoleucine, indicating abnormalities of both the glycine-cleavage system and branched-chain alpha-ketoacid dehydrogenase. In contrast, the activities of fibroblast pyruvate carboxylase, mitochondrial aconitase, and citrate synthase were normal. Immunoblot analysis of selected complex III subunits (core 1, cyt c(1), and iron-sulfur protein) and of the pyruvate dehydrogenase complex subunits revealed no visible changes in the levels of all examined proteins, decreasing the possibility that an import and/or assembly factor is involved. To elucidate the underlying molecular defect, analysis of microcell-mediated chromosome-fusion was performed between the present study's fibroblasts (recipients) and a panel of A9 mouse:human hybrids (donors) developed by Cuthbert et al. (1995). Complementation was observed between the recipient cells from both families and the mouse:human hybrid clone carrying human chromosome 2. These results indicate that the underlying defect in our patients is under the control of a nuclear gene, the locus of which is on chromosome 2. A 5-cM interval has been identified as potentially containing the critical region for the unknown gene. This interval maps to region 2p14-2p13.\n" ], "offsets": [ [ 0, 2128 ] ] } ]

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[ { "id": "11353403__text", "type": "abstract", "text": [ "Evaluation of candidate genes in case-control studies: a statistical method to account for related subjects. Traditional case-control studies provide a powerful and efficient method for evaluation of association between candidate genes and disease. The sampling of cases from multiplex pedigrees, rather than from a catchment area, can increase the likelihood that genetic cases are selected. However, use of all the related cases without accounting for their biological relationship can increase the type I error rate of the statistical test. To overcome this problem, we present an analysis method that is used to compare genotype frequencies between cases and controls, according to a trend in proportions as the dosage of the risk allele increases. This method uses the appropriate variance to account for the correlated family data, thus maintaining the correct type I error rate. The magnitude of the association is estimated by the odds ratio, with the variance of the odds ratio also accounting for the correlated data. Our method makes efficient use of data collected from multiplex families and should prove useful for the analysis of candidate genes among families sampled for linkage studies. An application of our method, to family data from a prostate cancer study, is presented to illustrate the method's utility.\n" ], "offsets": [ [ 0, 1329 ] ] } ]

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[ { "id": "11083946__text", "type": "abstract", "text": [ "The 28-kb deletion spanning D15S63 is a polymorphic variant in the Ashkenazi Jewish population. D15S63 is one of the loci, on chromosome 15q11-q13, that exhibit parent-of-origin dependent methylation and that is commonly used in the diagnosis of Prader-Willi or Angelman syndromes (PWS/AS). A 28-kb deletion spanning the D15S63 locus was identified in five unrelated patients; in each of them the deletion was inherited from a normal parent. Three of the five families segregating the deletion were reported to be of Jewish Ashkenazi ancestry, and in the other two families the ancestral origin was unknown. To determine whether the 28-kb deletion is a benign variant, we screened for the deletion in 137 unselected Ashkenazi individuals and in 268 patients who were referred for molecular diagnosis of PWS/AS, of whom 89 were Ashkenazi and 47 were of mixed origin (Ashkenazi and non-Ashkenazi Jews). In the control group, three individuals were carriers of the deletion; among the patients, three were carriers, all of whom were Ashkenazi Jews. There was no significant difference between the control group and the Ashkenazi patients, indicating that the deletion is not a cause of PWS- and AS-like syndromes. The frequency of the 28-kb deletion in the Ashkenazi population was 1/75. Since methylation analysis at the D15S63 locus may lead to misdiagnosis, we suggest the use of SNRPN, either in a PCR-based assay or as a probe in Southern hybridization, as the method of choice in the diagnosis of PWS/AS.\n" ], "offsets": [ [ 0, 1508 ] ] } ]

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[ { "id": "11283796__text", "type": "abstract", "text": [ "Disruption of the bipartite imprinting center in a family with Angelman syndrome. Imprinting in 15q11-q13 is controlled by a bipartite imprinting center (IC), which maps to the SNURF-SNRPN locus. Deletions of the exon 1 region impair the establishment or maintenance of the paternal imprint and can cause Prader-Willi syndrome (PWS). Deletions of a region 35 kb upstream of exon 1 impair maternal imprinting and can cause Angelman syndrome (AS). So far, in all affected sibs with an imprinting defect, an inherited IC deletion was identified. We report on two sibs with AS who do not have an IC deletion but instead have a 1-1.5 Mb inversion separating the two IC elements. The inversion is transmitted silently through the male germline but impairs maternal imprinting after transmission through the female germline. Our findings suggest that the close proximity and/or the correct orientation of the two IC elements are/is necessary for the establishment of a maternal imprint.\n" ], "offsets": [ [ 0, 980 ] ] } ]

[ { "id": "11283796_T1", "type": "Gene", "text": [ "SNURF-SNRPN" ], "offsets": [ [ 177, 188 ] ], "normalized": [] } ]

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[ { "id": "11333381__text", "type": "abstract", "text": [ "Niemann-Pick C1 disease: correlations between NPC1 mutations, levels of NPC1 protein, and phenotypes emphasize the functional significance of the putative sterol-sensing domain and of the cysteine-rich luminal loop. To obtain more information of the functional domains of the NPC1 protein, the mutational spectrum and the level of immunoreactive protein were investigated in skin fibroblasts from 30 unrelated patients with Niemann-Pick C1 disease. Nine of them were characterized by mild alterations of cellular cholesterol transport (the \"variant\" biochemical phenotype). The mutations showed a wide distribution to nearly all NPC1 domains, with a cluster (11/32) in a conserved NPC1 cysteine-rich luminal loop. Homozygous mutations in 14 patients and a phenotypically defined allele, combined with a new mutation, in a further 10 patients allowed genotype/phenotype correlations. Premature-termination-codon mutations, the three missense mutations in the sterol-sensing domain (SSD), and A1054T in the cysteine-rich luminal loop all occurred in patients with infantile neurological onset and \"classic\" (severe) cholesterol-trafficking alterations. By western blot, NPC1 protein was undetectable in the SSD missense mutations studied (L724P and Q775P) and essentially was absent in the A1054T missense allele. Our results thus enhance the functional significance of the SSD and demonstrate a correlation between the absence of NPC1 protein and the most severe neurological form. In the remaining missense mutations studied, corresponding to other disease presentations (including two adults with nonneurological disease), NPC1 protein was present in significant amounts of normal size, without clear-cut correlation with either the clinical phenotype or the \"classic\"/\"variant\" biochemical phenotype. Missense mutations in the cysteine-rich luminal loop resulted in a wide array of clinical and biochemical phenotypes. Remarkably, all five mutant alleles (I943M, V950M, G986S, G992R, and the recurrent P1007A) definitively correlated with the \"variant\" phenotype clustered within this loop, providing new insight on the functional complexity of the latter domain.\n" ], "offsets": [ [ 0, 2166 ] ] } ]

[ { "id": "11333381_T1", "type": "Gene", "text": [ "NPC1" ], "offsets": [ [ 46, 50 ] ], "normalized": [] }, { "id": "11333381_T2", "type": "Gene", "text": [ "NPC1" ], "offsets": [ [ 72, 76 ] ], "normalized": [] }, { "id": "11333381_T3", "type": "Gene", "text": [ "NPC1" ], "offsets": [ [ 276, 280 ] ], "normalized": [] }, { "id": "11333381_T4", "type": "Gene", "text": [ "NPC1" ], "offsets": [ [ 681, 685 ] ], "normalized": [] }, { "id": "11333381_T5", "type": "Gene", "text": [ "NPC1" ], "offsets": [ [ 629, 633 ] ], "normalized": [] }, { "id": "11333381_T6", "type": "SNP", "text": [ "A1054T" ], "offsets": [ [ 991, 997 ] ], "normalized": [] }, { "id": "11333381_T7", "type": "Gene", "text": [ "NPC1" ], "offsets": [ [ 1168, 1172 ] ], "normalized": [] }, { "id": "11333381_T8", "type": "SNP", "text": [ "L724P" ], "offsets": [ [ 1237, 1242 ] ], "normalized": [] }, { "id": "11333381_T9", "type": "SNP", "text": [ "Q775P" ], "offsets": [ [ 1247, 1252 ] ], "normalized": [] }, { "id": "11333381_T10", "type": "SNP", "text": [ "A1054T" ], "offsets": [ [ 1288, 1294 ] ], "normalized": [] }, { "id": "11333381_T11", "type": "Gene", "text": [ "NPC1" ], "offsets": [ [ 1429, 1433 ] ], "normalized": [] }, { "id": "11333381_T12", "type": "Gene", "text": [ "NPC1" ], "offsets": [ [ 1624, 1628 ] ], "normalized": [] }, { "id": "11333381_T13", "type": "SNP", "text": [ "I943M" ], "offsets": [ [ 1958, 1963 ] ], "normalized": [] }, { "id": "11333381_T17", "type": "SNP", "text": [ "P1007A" ], "offsets": [ [ 2004, 2010 ] ], "normalized": [] }, { "id": "11333381_T14", "type": "SNP", "text": [ "V950M" ], "offsets": [ [ 1965, 1970 ] ], "normalized": [] }, { "id": "11333381_T15", "type": "SNP", "text": [ "G986S" ], "offsets": [ [ 1972, 1977 ] ], "normalized": [] }, { "id": "11333381_T16", "type": "SNP", "text": [ "G992R" ], "offsets": [ [ 1979, 1984 ] ], "normalized": [] } ]

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[ { "id": "11443547__text", "type": "abstract", "text": [ "Mutations in the sepiapterin reductase gene cause a novel tetrahydrobiopterin-dependent monoamine-neurotransmitter deficiency without hyperphenylalaninemia. Classic tetrahydrobiopterin (BH(4)) deficiencies are characterized by hyperphenylalaninemia and deficiency of monoamine neurotransmitters. In this article, we report two patients with progressive psychomotor retardation, dystonia, severe dopamine and serotonin deficiencies (low levels of 5-hydroxyindoleacetic and homovanillic acids), and abnormal pterin pattern (high levels of biopterin and dihydrobiopterin) in cerebrospinal fluid. Furthermore, they presented with normal urinary pterins and without hyperphenylalaninemia. Investigation of skin fibroblasts revealed inactive sepiapterin reductase (SR), the enzyme catalyzing the final two-step reaction in the biosynthesis of BH(4). Mutations in the SPR gene were detected in both patients and their family members. One patient was homozygous for a TC-->CT dinucleotide exchange, predicting a truncated SR (Q119X). The other patient was a compound heterozygote for a genomic 5-bp deletion (1397-1401delAGAAC) resulting in abolished SPR-gene expression and an A-->G transition leading to an R150G amino acid substitution and to inactive SR as confirmed by recombinant expression. The absence of hyperphenylalaninemia and the presence of normal urinary pterin metabolites and of normal SR-like activity in red blood cells may be explained by alternative pathways for the final two-step reaction of BH(4) biosynthesis in peripheral and neuronal tissues. We propose that, for the biosynthesis of BH(4) in peripheral tissues, SR activity may be substituted by aldose reductase (AR), carbonyl reductase (CR), and dihydrofolate reductase, whereas, in the brain, only AR and CR are fully present. Thus, autosomal recessive SR deficiency leads to BH(4) and to neurotransmitter deficiencies without hyperphenylalaninemia and may not be detected by neonatal screening for phenylketonuria.\n" ], "offsets": [ [ 0, 1989 ] ] } ]

[ { "id": "11443547_T1", "type": "Gene", "text": [ "sepiapterin reductase" ], "offsets": [ [ 17, 38 ] ], "normalized": [] }, { "id": "11443547_T2", "type": "Gene", "text": [ "SPR" ], "offsets": [ [ 861, 864 ] ], "normalized": [] }, { "id": "11443547_T3", "type": "SNP", "text": [ "Q119X" ], "offsets": [ [ 1018, 1023 ] ], "normalized": [] }, { "id": "11443547_T4", "type": "SNP", "text": [ "1397-1401delAGAAC" ], "offsets": [ [ 1101, 1118 ] ], "normalized": [] }, { "id": "11443547_T5", "type": "Gene", "text": [ "SPR-gene" ], "offsets": [ [ 1143, 1151 ] ], "normalized": [] }, { "id": "11443547_T6", "type": "SNP", "text": [ "R150G" ], "offsets": [ [ 1201, 1206 ] ], "normalized": [] }, { "id": "11443547_T7", "type": "Gene", "text": [ "aldose reductase" ], "offsets": [ [ 1666, 1682 ] ], "normalized": [] }, { "id": "11443547_T8", "type": "Gene", "text": [ "carbonyl reductase" ], "offsets": [ [ 1689, 1707 ] ], "normalized": [] }, { "id": "11443547_T9", "type": "Gene", "text": [ "AR" ], "offsets": [ [ 1684, 1686 ] ], "normalized": [] }, { "id": "11443547_T10", "type": "Gene", "text": [ "CR" ], "offsets": [ [ 1709, 1711 ] ], "normalized": [] }, { "id": "11443547_T11", "type": "Gene", "text": [ "dihydrofolate reductase" ], "offsets": [ [ 1718, 1741 ] ], "normalized": [] } ]

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[ { "id": "11309687__text", "type": "abstract", "text": [ "A confidence-set approach for finding tightly linked genomic regions. As more studies adopt the approach of whole-genome screening, geneticists are faced with the challenge of having to interpret results from traditional approaches that were not designed for genome-scan data. Frequently, two-point analysis by the LOD method is performed to search for signals of linkage throughout the genome, for each of hundreds or even thousands of markers. This practice has raised the question of how to adjust the significance level for the fact that multiple tests are being performed. Various recommendations have been made, but no consensus has emerged. In this article, we propose a new method, the confidence-set approach, that circumvents the need to correct for the level of significance according to the number of markers tested. In the search for the gene location of a monogenic disorder, multiplicity adjustment is not needed in order to maintain the desired level of confidence. For complex diseases involving multiple genes, one needs only to adjust the level of significance according to the number of disease genes--a much smaller number than the number of markers in a genome screen-to ensure a predetermined genomewide confidence level. Furthermore, our formulation of the tests enables us to localize disease genes to small genomic regions, an extremely desirable feature that the traditional LOD method lacks. Our simulation study shows that, for sib-pair data, even when the coverage probability of the confidence set is chosen to be as high as 99%, our approach is able to implicate only the markers that are closely linked to the disease genes.\n" ], "offsets": [ [ 0, 1658 ] ] } ]

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[ { "id": "11410843__text", "type": "abstract", "text": [ "The presence of mitochondrial haplogroup x in Altaians from South Siberia.\n" ], "offsets": [ [ 0, 75 ] ] } ]

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[ { "id": "11083947__text", "type": "abstract", "text": [ "Extent and distribution of linkage disequilibrium in three genomic regions. The positional cloning of genes underlying common complex diseases relies on the identification of linkage disequilibrium (LD) between genetic markers and disease. We have examined 127 polymorphisms in three genomic regions in a sample of 575 chromosomes from unrelated individuals of British ancestry. To establish phase, 800 individuals were genotyped in 160 families. The fine structure of LD was found to be highly irregular. Forty-five percent of the variation in disequilibrium measures could be explained by physical distance. Additional factors, such as allele frequency, type of polymorphism, and genomic location, explained <5% of the variation. Nevertheless, disequilibrium was occasionally detectable at 500 kb and was present for over one-half of marker pairs separated by <50 kb. Although these findings are encouraging for the prospects of a genomewide LD map, they suggest caution in interpreting localization due to allelic association.\n" ], "offsets": [ [ 0, 1030 ] ] } ]

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[ { "id": "11179004__text", "type": "abstract", "text": [ "Connexin mutations in skin disease and hearing loss.\n" ], "offsets": [ [ 0, 53 ] ] } ]

[ { "id": "11179004_T1", "type": "Gene", "text": [ "Connexin" ], "offsets": [ [ 0, 8 ] ], "normalized": [] } ]

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[ { "id": "11519010__text", "type": "abstract", "text": [ "Evidence of linkage with HLA-DR in DRB1*15-negative families with multiple sclerosis. The importance of the HLA-DR locus to multiple sclerosis (MS) susceptibility was assessed in 542 sib pairs with MS and in their families. By genotyping 1,978 individuals for HLA-DRB1 alleles, we confirmed the well-established association of MS with HLA-DRB1*15 (HLA-DRB1*1501 and HLA-DRB5*0101), by the transmission/disequilibrium test (chi2=138.3; P<.0001). We obtained significant evidence of linkage throughout the whole data set (mlod=4.09; 59.9% sharing). Surprisingly, similar sharing was also observed in 58 families in which both parents lacked the DRB1*15 allele (mlod=1.56; 62.7% sharing; P=.0081). Our findings suggest that the notion that HLA-DRB1*15 is the sole major-histocompatibility-complex determinant of susceptibility in northern-European populations with MS may be incorrect. It remains possible that the association of MS with HLA-DRB1*15 is due to linkage disequilibrium with a nearby locus and/or to the presence of disease-influencing allele(s) in DRB1*15-negative haplotypes.\n" ], "offsets": [ [ 0, 1088 ] ] } ]

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[ { "id": "11509994__text", "type": "abstract", "text": [ "Maple syrup urine disease: identification and carrier-frequency determination of a novel founder mutation in the Ashkenazi Jewish population. Maple syrup urine disease (MSUD) is a rare, autosomal recessive disorder of branched-chain amino acid metabolism. We noted that a large proportion (10 of 34) of families with MSUD that were followed in our clinic were of Ashkenazi Jewish (AJ) descent, leading us to search for a common mutation within this group. On the basis of genotyping data suggestive of a conserved haplotype at tightly linked markers on chromosome 6q14, the BCKDHB gene encoding the E1beta subunit was sequenced. Three novel mutations were identified in seven unrelated AJ patients with MSUD. The locations of the affected residues in the crystal structure of the E1beta subunit suggested possible mechanisms for the deleterious effects of these mutations. Large-scale population screening of AJ individuals for R183P, the mutation present in six of seven patients, revealed that the carrier frequency of the mutant allele was approximately 1/113; the patient not carrying R183P had a previously described homozygous mutation in the gene encoding the E2 subunit. These findings suggested that a limited number of mutations might underlie MSUD in the AJ population, potentially facilitating prenatal diagnosis and carrier detection of MSUD in this group.\n" ], "offsets": [ [ 0, 1370 ] ] } ]

[ { "id": "11509994_T1", "type": "SNP", "text": [ "R183P" ], "offsets": [ [ 928, 933 ] ], "normalized": [] }, { "id": "11509994_T2", "type": "Gene", "text": [ "BCKDHB" ], "offsets": [ [ 574, 580 ] ], "normalized": [] }, { "id": "11509994_T3", "type": "SNP", "text": [ "R183P" ], "offsets": [ [ 1089, 1094 ] ], "normalized": [] } ]

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[ { "id": "11509994_R1", "type": "AssociatedTo", "arg1_id": "11509994_T1", "arg2_id": "11509994_T2", "normalized": [] }, { "id": "11509994_R2", "type": "AssociatedTo", "arg1_id": "11509994_T3", "arg2_id": "11509994_T2", "normalized": [] } ]

[ { "id": "11179018__text", "type": "abstract", "text": [ "A phase 1/2 clinical trial of enzyme replacement in fabry disease: pharmacokinetic, substrate clearance, and safety studies. Fabry disease results from deficient alpha-galactosidase A (alpha-Gal A) activity and the pathologic accumulation of the globotriaosylceramide (GL-3) and related glycosphingolipids, primarily in vascular endothelial lysosomes. Treatment is currently palliative, and affected patients generally die in their 40s or 50s. Preclinical studies of recombinant human alpha-Gal A (r-halphaGalA) infusions in knockout mice demonstrated reduction of GL-3 in tissues and plasma, providing rationale for a phase 1/2 clinical trial. Here, we report a single-center, open-label, dose-ranging study of r-halphaGalA treatment in 15 patients, each of whom received five infusions at one of five dose regimens. Intravenously administered r-halphaGalA was cleared from the circulation in a dose-dependent manner, via both saturable and non-saturable pathways. Rapid and marked reductions in plasma and tissue GL-3 were observed biochemically, histologically, and/or ultrastructurally. Clearance of plasma GL-3 was dose-dependent. In patients with pre- and posttreatment biopsies, mean GL-3 content decreased 84% in liver (n=13), was markedly reduced in kidney in four of five patients, and after five doses was modestly lowered in the endomyocardium of four of seven patients. GL-3 deposits were cleared to near normal or were markedly reduced in the vascular endothelium of liver, skin, heart, and kidney, on the basis of light- and electron-microscopic evaluation. In addition, patients reported less pain, increased ability to sweat, and improved quality-of-life measures. Infusions were well tolerated; four patients experienced mild-to-moderate reactions, suggestive of hypersensitivity, that were managed conservatively. Of 15 patients, 8 (53%) developed IgG antibodies to r-halphaGalA; however, the antibodies were not neutralizing, as indicated by unchanged pharmacokinetic values for infusions 1 and 5. This study provides the basis for a phase 3 trial of enzyme-replacement therapy for Fabry disease.\n" ], "offsets": [ [ 0, 2117 ] ] } ]

[ { "id": "11179018_T1", "type": "Gene", "text": [ "alpha-Gal A" ], "offsets": [ [ 485, 496 ] ], "normalized": [] }, { "id": "11179018_T2", "type": "Gene", "text": [ "r-halphaGalA" ], "offsets": [ [ 498, 510 ] ], "normalized": [] }, { "id": "11179018_T3", "type": "Gene", "text": [ "GL-3" ], "offsets": [ [ 565, 569 ] ], "normalized": [] }, { "id": "11179018_T4", "type": "Gene", "text": [ "r-halphaGalA" ], "offsets": [ [ 712, 724 ] ], "normalized": [] }, { "id": "11179018_T5", "type": "Gene", "text": [ "r-halphaGalA" ], "offsets": [ [ 845, 857 ] ], "normalized": [] }, { "id": "11179018_T6", "type": "Gene", "text": [ "GL-3" ], "offsets": [ [ 1015, 1019 ] ], "normalized": [] }, { "id": "11179018_T7", "type": "Gene", "text": [ "GL-3" ], "offsets": [ [ 1111, 1115 ] ], "normalized": [] }, { "id": "11179018_T8", "type": "Gene", "text": [ "GL-3" ], "offsets": [ [ 1191, 1195 ] ], "normalized": [] }, { "id": "11179018_T9", "type": "Gene", "text": [ "GL-3" ], "offsets": [ [ 1383, 1387 ] ], "normalized": [] } ]

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[ { "id": "11179018_R1", "type": "Equals", "arg1_id": "11179018_T1", "arg2_id": "11179018_T2", "normalized": [] } ]

[ { "id": "11536080__text", "type": "abstract", "text": [ "Genomewide-linkage and haplotype-association studies map intracranial aneurysm to chromosome 7q11. Rupture of intracranial aneurysms (IAs) causes subarachnoid hemorrhage, a devastating condition with high morbidity and mortality. Angiographic and autopsy studies show that IA is a common disorder, with a prevalence of 3%-6%. Although IA has a substantial genetic component, little attention has been given to the genetic determinants. We report here a genomewide linkage study of IA in 104 Japanese affected sib pairs in which positive evidence of linkage on chromosomes 5q22-31 (maximum LOD score [MLS] 2.24), 7q11 (MLS 3.22), and 14q22 (MLS 2.31) were found. The best evidence of linkage is detected at D7S2472, in the vicinity of the elastin gene (ELN), a candidate gene for IA. Fourteen distinct single-nucleotide polymorphisms (SNPs) were identified in ELN, and no obvious allelic association between IA and each SNP was observed. The haplotype between the intron-20/intron-23 polymorphism of ELN is strongly associated with IA (P=3.81x10-6), and homozygous patients are at high risk (P=.002), with an odds ratio of 4.39. These findings suggest that a genetic locus for IA lies within or close to the ELN locus on chromosome 7.\n" ], "offsets": [ [ 0, 1234 ] ] } ]

[ { "id": "11536080_T1", "type": "SNP", "text": [ "D7S2472" ], "offsets": [ [ 706, 713 ] ], "normalized": [] }, { "id": "11536080_T2", "type": "Gene", "text": [ "elastin" ], "offsets": [ [ 738, 745 ] ], "normalized": [] }, { "id": "11536080_T3", "type": "Gene", "text": [ "ELN" ], "offsets": [ [ 752, 755 ] ], "normalized": [] }, { "id": "11536080_T4", "type": "Gene", "text": [ "ELN," ], "offsets": [ [ 859, 863 ] ], "normalized": [] }, { "id": "11536080_T5", "type": "Gene", "text": [ "ELN" ], "offsets": [ [ 999, 1002 ] ], "normalized": [] }, { "id": "11536080_T6", "type": "Gene", "text": [ "ELN" ], "offsets": [ [ 1207, 1210 ] ], "normalized": [] } ]

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[ { "id": "11536080_R1", "type": "Equals", "arg1_id": "11536080_T2", "arg2_id": "11536080_T3", "normalized": [] }, { "id": "11536080_R2", "type": "AssociatedTo", "arg1_id": "11536080_T1", "arg2_id": "11536080_T3", "normalized": [] } ]

[ { "id": "11254449__text", "type": "abstract", "text": [ "HPC2 variants and screen-detected prostate cancer. Two studies have reported significant associations between susceptibility to prostate cancer and two common missense variants of the HPC2/ELAC2 gene, with estimated relative risks in the range of two- to threefold. We investigated whether these polymorphisms could be informative in the prediction of the presence of prostate cancer in men undergoing prostatic biopsy for the evaluation of an elevated serum-PSA level (> or = 4.0 ng/ml). We genotyped 944 men who underwent a prostate biopsy at our institution, as well as a control population of 922 healthy, unselected women from the same population. The prevalence of the HPC2 Ala541Thr allele was similar in men with prostate cancer (6.3%), men with other prostatic conditions (6.8%), and healthy women (6.3%) (P = .83). We conclude that HPC2 genotyping is unlikely to be a useful adjunct to PSA in the prediction of the presence of biopsy-detected prostate cancer in asymptomatic men.\n" ], "offsets": [ [ 0, 990 ] ] } ]

[ { "id": "11254449_T1", "type": "Gene", "text": [ "HPC2" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "11254449_T2", "type": "Gene", "text": [ "HPC2" ], "offsets": [ [ 184, 188 ] ], "normalized": [] }, { "id": "11254449_T3", "type": "Gene", "text": [ "HPC2" ], "offsets": [ [ 675, 679 ] ], "normalized": [] }, { "id": "11254449_T4", "type": "SNP", "text": [ "Ala541Thr" ], "offsets": [ [ 680, 689 ] ], "normalized": [] }, { "id": "11254449_T5", "type": "Gene", "text": [ "HPC2" ], "offsets": [ [ 842, 846 ] ], "normalized": [] }, { "id": "11254449_T6", "type": "Gene", "text": [ "ELAC2" ], "offsets": [ [ 189, 194 ] ], "normalized": [] } ]

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[ { "id": "11254449_R1", "type": "AssociatedTo", "arg1_id": "11254449_T4", "arg2_id": "11254449_T3", "normalized": [] } ]

[ { "id": "11309680__text", "type": "abstract", "text": [ "Identification of a new candidate locus for uric acid nephrolithiasis. Renal stone formation is a common multifactorial disorder, of unknown etiology, with an established genetic contribution. Lifetime risk for nephrolithiasis is approximately 10% in Western populations, and uric acid stones account for 5%-10% of all stones, depending on climatic, dietary, and ethnic differences. We studied a small, isolated founder population in Sardinia, characterized by an increased prevalence of uric acid stones, and performed a genomewide search in a deep-rooted pedigree comprising many members who formed uric acid renal stones. The pedigree was created by tracing common ancestors of affected individuals through a genealogical database based on archival records kept by the parish church since 1640. This genealogical information was used as the basis for the study strategy, involving screening for alleles shared among affected individuals, originating from common ancestors, and utilization of large pedigrees to obtain greater power for linkage detection. We performed multistep linkage and allele-sharing analyses. In the initial stage, 382 markers were typed in 14 closely related affected subjects; interesting regions were subsequently investigated in the whole sample. We identified two chromosomal regions that may harbor loci with susceptibility genes for uric acid stones. The strongest evidence was observed on 10q21-q22, where a LOD score of 3.07 was obtained for D10S1652 under an affected-only dominant model, and a LOD score of 3.90 was obtained using a dominant pseudomarker assignment. The localization was supported also by multipoint allele-sharing statistics and by haplotype analysis of familial cases and of unrelated affected subjects collected from the isolate. In the second region on 20q13.1-13.3, multipoint nonparametric scores yielded suggestive evidence in a approximately 20-cM region, and further analysis is needed to confirm and fine-map this putative locus. Replication studies are required to investigate the involvement of these regions in the genetic contribution to uric acid stone formation.\n" ], "offsets": [ [ 0, 2132 ] ] } ]

[ { "id": "11309680_T1", "type": "SNP", "text": [ "D10S1652" ], "offsets": [ [ 1476, 1484 ] ], "normalized": [] } ]

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[ { "id": "8352278__text", "type": "abstract", "text": [ "Statistical evaluation of multiple-locus linkage data in experimental species and its relevance to human studies: application to nonobese diabetic (NOD) mouse and human insulin-dependent diabetes mellitus (IDDM). Common, familial human disorders generally do not follow Mendelian inheritance patterns, presumably because multiple loci are involved in disease susceptibility. One approach to mapping genes for such traits in humans is to first study an analogous form in an animal model, such as mouse, by using inbred strains and backcross experiments. Here we describe methodology for analyzing multiple-locus linkage data from such experimental backcrosses, particularly in light of multilocus genetic models, including the effects of epistasis. We illustrate these methods by using data from backcrosses involving nonobese diabetic mouse, which serves as an animal model for human insulin-dependent diabetes mellitus. We show that it is likely that a minimum of nine loci contribute to susceptibility, with strong epistasis effects among these loci. Three of the loci actually confer a protective effect in the homozygote, compared with the heterozygote. Further, we discuss the relevance of these studies for analogous studies of the human form of the trait. Specifically, we show that the magnitude of the gene effect in the experimental backcross is likely to correlate only weakly, at best, with the expected magnitude of effect for a human form, because in humans the gene effect will depend more heavily on disease allele frequencies than on the observed penetrance ratios; such allele frequencies are unpredictable. Hence, the major benefit from animal studies may be a better understanding of the disease process itself, rather than identification of cells through comparison mapping in humans by using regions of homology.\n" ], "offsets": [ [ 0, 1835 ] ] } ]

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[ { "id": "8328463__text", "type": "abstract", "text": [ "American College of Medical Genetics. Prenatal interphase fluorescence in situ hybridization (FISH) policy statement.\n" ], "offsets": [ [ 0, 118 ] ] } ]

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[ { "id": "8434583__text", "type": "abstract", "text": [ "Germ-line origins of mutation in families with hemophilia B: the sex ratio varies with the type of mutation. Previous epidemiological and biochemical studies have generated conflicting estimates of the sex ratio of mutation. Direct genomic sequencing in combination with haplotype analysis extends previous analyses by allowing the precise mutation to be determined in a given family. From analysis of the factor IX gene of 260 consecutive families with hemophilia B, we report the germ-line origin of mutation in 25 families. When combined with 14 origins of mutation reported by others and with 4 origins previously reported by us, a total of 25 occur in the female germ line, and 18 occur in the male germ line. The excess of germ-line origins in females does not imply an overall excess mutation rate per base pair in the female germ line. Bayesian analysis of the data indicates that the sex ratio varies with the type of mutation. The aggregate of single-base substitutions shows a male predominance of germ-line mutations (P < .002). The maximum-likelihood estimate of the male predominance is 3.5-fold. Of the single-base substitutions, transitions at the dinucleotide CpG show the largest male predominance (11-fold). In contrast to single-base substitutions, deletions display a sex ratio of unity. Analysis of the parental age at transmission of a new mutation suggests that germ-line mutations are associated with a small increase in parental age in females but little, if any, increase in males. Although direct genomic sequencing offers a general method for defining the origin of mutation in specific families, accurate estimates of the sex ratios of different mutational classes require large sample sizes and careful correction for multiple biases of ascertainment. The biases in the present data result in an underestimate of the enhancement of mutation in males.\n" ], "offsets": [ [ 0, 1882 ] ] } ]

[ { "id": "8434583_T1", "type": "Gene", "text": [ "factor IX" ], "offsets": [ [ 406, 415 ] ], "normalized": [] } ]

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[ { "id": "8434594__text", "type": "abstract", "text": [ "Educating the medical community through a teratology newsletter. To educate a geographically and professionally diverse group of health care providers about teratology in an economic and efficient manner, we developed a locally written and distributed teratology newsletter. Response to the newsletter, from readers as well as from our staff and funding agencies, suggests that such a newsletter can be a valuable tool in educating medical communities about teratology.\n" ], "offsets": [ [ 0, 470 ] ] } ]

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[ { "id": "8352283__text", "type": "abstract", "text": [ "Better data analysis through data exploration.\n" ], "offsets": [ [ 0, 47 ] ] } ]

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[ { "id": "8430703__text", "type": "abstract", "text": [ "The postulated X-inactivation center at Xq27 is most reasonably explained by ascertainment bias: heterozygous expression of recessive mutations is a powerful means of detecting unbalanced X inactivation.\n" ], "offsets": [ [ 0, 204 ] ] } ]

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[ { "id": "8460646__text", "type": "abstract", "text": [ "BRCA1 maps proximal to D17S579 on chromosome 17q21 by genetic analysis. Previous studies have demonstrated linkage between early-onset breast cancer and ovarian cancer and genetic markers on chromosome 17q21. These markers define the location of a gene (BRCA1) which appears to be inherited as an autosomal dominant susceptibility allele. We analyzed five families with multiple affected individuals for evidence of linkage to the BRCA1 region. Two of the five families appear to be linked to BRCA1. One apparently linked family contains critical recombinants, suggesting that the gene is proximal to the marker D17S579 (Mfd188). These findings are consistent with the maximum-likelihood position estimated by the Breast Cancer Linkage Consortium and with recombination events detected in other linked families. Linkage analysis was greatly aided by PCR-based analysis of paraffin-embedded normal breast tissue from deceased family members, demonstrating the feasibility and importance of this approach. One of the two families with evidence of linkage between breast cancer and genetic markers flanking BRCA1 represents the first such family of African-American descent to be reported in detail.\n" ], "offsets": [ [ 0, 1197 ] ] } ]

[ { "id": "8460646_T1", "type": "Gene", "text": [ "BRCA1" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "8460646_T2", "type": "Gene", "text": [ "BRCA1" ], "offsets": [ [ 254, 259 ] ], "normalized": [] }, { "id": "8460646_T3", "type": "Gene", "text": [ "BRCA1" ], "offsets": [ [ 431, 436 ] ], "normalized": [] }, { "id": "8460646_T4", "type": "Gene", "text": [ "BRCA1" ], "offsets": [ [ 493, 498 ] ], "normalized": [] }, { "id": "8460646_T5", "type": "Gene", "text": [ "BRCA1" ], "offsets": [ [ 1104, 1109 ] ], "normalized": [] } ]

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[ { "id": "8102508__text", "type": "abstract", "text": [ "Genetic heterogeneity in benign familial neonatal convulsions: identification of a new locus on chromosome 8q. The syndrome of benign familial neonatal convulsions (BFNC) is a rare autosomal dominant disorder characterized by unprovoked seizures in the first few weeks of life. One locus for BFNC has been mapped to chromosome 20 in several pedigrees, but we have excluded linkage to chromosome 20 in one large kindred. In order to identify this novel BFNC locus, dinucleotide repeat markers distributed throughout the genome were used to screen this family. Maximum pairwise LOD scores of 4.43 were obtained with markers D8S284 and D8S256 on chromosome 8q. Multipoint analysis placed the BFNC locus in the interval spanned by D8S198-D8S274. This study establishes the presence of a new BFNC locus and confirms genetic heterogeneity of this disorder.\n" ], "offsets": [ [ 0, 851 ] ] } ]

[ { "id": "8102508_T1", "type": "Gene", "text": [ "BFNC" ], "offsets": [ [ 292, 296 ] ], "normalized": [] }, { "id": "8102508_T2", "type": "Gene", "text": [ "BFNC" ], "offsets": [ [ 452, 456 ] ], "normalized": [] }, { "id": "8102508_T3", "type": "Gene", "text": [ "BFNC" ], "offsets": [ [ 689, 693 ] ], "normalized": [] }, { "id": "8102508_T4", "type": "Gene", "text": [ "BFNC" ], "offsets": [ [ 787, 791 ] ], "normalized": [] } ]

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[ { "id": "8105686__text", "type": "abstract", "text": [ "High prevalence of the point mutation in exon 6 of the xeroderma pigmentosum group A-complementing (XPAC) gene in xeroderma pigmentosum group A patients in Tunisia. Xeroderma pigmentosum (XP) patients in Tunisia who belong to the genetic complementation group A (XPA) have milder skin symptoms than do Japanese XPA patients. Such difference in the clinical features might be caused by the difference in the site of mutation in the XP A-complementing (XPAC) gene. The purpose of this study is to identify the genetic alterations in the XPAC gene in the Tunisian XPA patients and to investigate the relationship between the clinical symptoms and the genetic alterations. Three sites of mutation in the XPAC gene have been identified in the Japanese XPA patients, and about 85% of them have a G-->C point mutation at the splicing acceptor site of intron 3. We found that six (86%) of seven Tunisian XPA patients had a nonsense mutation in codon 228 in exon 6, because of a CGA-->TGA point mutation, which can be detected by the HphI RFLP. This type of mutation is the same as those found in two Japanese XPA patients with mild clinical symptoms. Milder skin symptoms in the XPA patients in Tunisia than in those in Japan, despite mostly sunny weather and the unsatisfactory sun protection in Tunisia, should be due to the difference in the mutation site.\n" ], "offsets": [ [ 0, 1352 ] ] } ]

[ { "id": "8105686_T1", "type": "Gene", "text": [ "xeroderma pigmentosum group A-complementing" ], "offsets": [ [ 55, 98 ] ], "normalized": [] }, { "id": "8105686_T2", "type": "Gene", "text": [ "XPAC" ], "offsets": [ [ 100, 104 ] ], "normalized": [] }, { "id": "8105686_T3", "type": "Gene", "text": [ "XPAC" ], "offsets": [ [ 451, 455 ] ], "normalized": [] }, { "id": "8105686_T4", "type": "Gene", "text": [ "XP A-complementing" ], "offsets": [ [ 431, 449 ] ], "normalized": [] }, { "id": "8105686_T5", "type": "Gene", "text": [ "XPAC" ], "offsets": [ [ 535, 539 ] ], "normalized": [] }, { "id": "8105686_T6", "type": "Gene", "text": [ "XPAC" ], "offsets": [ [ 700, 704 ] ], "normalized": [] }, { "id": "8105686_T7", "type": "SNP", "text": [ "codon 228 in exon 6, because of a CGA-->TGA" ], "offsets": [ [ 936, 979 ] ], "normalized": [] } ]

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[ { "id": "8105686_R1", "type": "Equals", "arg1_id": "8105686_T1", "arg2_id": "8105686_T2", "normalized": [] }, { "id": "8105686_R2", "type": "Equals", "arg1_id": "8105686_T4", "arg2_id": "8105686_T3", "normalized": [] }, { "id": "8105686_R3", "type": "AssociatedTo", "arg1_id": "8105686_T7", "arg2_id": "8105686_T6", "normalized": [] } ]

[ { "id": "8352275__text", "type": "abstract", "text": [ "Linkage analysis of idiopathic generalized epilepsy (IGE) and marker loci on chromosome 6p in families of patients with juvenile myoclonic epilepsy: no evidence for an epilepsy locus in the HLA region. Evidence for a locus (EJM1) in the HLA region of chromosome 6p predisposing to idiopathic generalized epilepsy (IGE) in the families of patients with juvenile myoclonic epilepsy (JME) has been obtained in two previous studies of separately ascertained groups of kindreds. Linkage analysis has been undertaken in a third set of 25 families including a patient with JME and at least one first-degree relative with IGE. Family members were typed for eight polymorphic loci on chromosome 6p: F13A, D6S89, D6S109, D6S105, D6S10, C4B, DQA1/A2, and TCTE1. Pairwise and multipoint linkage analysis was carried out assuming autosomal dominant and autosomal recessive inheritance and age-dependent high or low penetrance. No significant evidence in favor of linkage was obtained at any locus. Multipoint linkage analysis generated significant exclusion data (lod score < -2.0) at HLA and for a region 10-30 cM telomeric to HLA, the extent of which varied with the level of penetrance assumed. These observations indicate that genetic heterogeneity exists within this epilepsy phenotype.\n" ], "offsets": [ [ 0, 1279 ] ] } ]

[ { "id": "8352275_T1", "type": "Gene", "text": [ "EJM1" ], "offsets": [ [ 224, 228 ] ], "normalized": [] }, { "id": "8352275_T2", "type": "Gene", "text": [ "TCTE1" ], "offsets": [ [ 744, 749 ] ], "normalized": [] }, { "id": "8352275_T3", "type": "SNP", "text": [ "F13A" ], "offsets": [ [ 690, 694 ] ], "normalized": [] }, { "id": "8352275_T4", "type": "SNP", "text": [ "D6S89" ], "offsets": [ [ 696, 701 ] ], "normalized": [] }, { "id": "8352275_T5", "type": "SNP", "text": [ "D6S109" ], "offsets": [ [ 703, 709 ] ], "normalized": [] }, { "id": "8352275_T6", "type": "SNP", "text": [ "D6S105" ], "offsets": [ [ 711, 717 ] ], "normalized": [] }, { "id": "8352275_T7", "type": "SNP", "text": [ "D6S10" ], "offsets": [ [ 719, 724 ] ], "normalized": [] }, { "id": "8352275_T8", "type": "SNP", "text": [ "C4B" ], "offsets": [ [ 726, 729 ] ], "normalized": [] }, { "id": "8352275_T9", "type": "SNP", "text": [ "DQA1/A2" ], "offsets": [ [ 731, 738 ] ], "normalized": [] } ]

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[ { "id": "8503437__text", "type": "abstract", "text": [ "X-linked mental retardation: in pursuit of a gene map.\n" ], "offsets": [ [ 0, 55 ] ] } ]

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[ { "id": "8488836__text", "type": "abstract", "text": [ "Rapid prenatal diagnosis of chromosomal aneuploidies by fluorescence in situ hybridization: clinical experience with 4,500 specimens. Detection of chromosome aneuploidies in uncultured amniocytes is possible using fluorescence in situ hybridization (FISH). We herein describe the results of the first clinical program which utilized FISH for the rapid detection of chromosome aneuploidies in uncultured amniocytes. FISH was performed on physician request, as an adjunct to cytogenetics in 4,500 patients. Region-specific DNA probes to chromosomes 13, 18, 21, X, and Y were used to determine ploidy by analysis of signal number in hybridized nuclei. A sample was considered to be euploid when all autosomal probes generated two hybridization signals and when a normal sex chromosome pattern was observed in greater than or equal to 80% of hybridized nuclei. A sample was considered to be aneuploid when greater than or equal to 70% of hybridized nuclei displayed the same abnormal hybridization pattern for a specific probe. Of the attempted analyses, 90.2% met these criteria and were reported as informative to referring physicians within 2 d of receipt. Based on these reporting parameters, the overall detection rate for aneuploidies was 73.3% (107/146), with an accuracy of informative results for aneuploidies of 93.9% (107/114). Compared to cytogenetics, the accuracy of all informative FISH results, euploid and aneuploid, was 99.8%, and the specificity was 99.9%. In those pregnancies where fetal abnormalities had been observed by ultrasound, referring physicians requested FISH plus cytogenetics at a significantly higher rate than they requested cytogenetics alone. The current prenatal FISH protocol is not designed to detect all chromosome abnormalities and should only be utilized as an adjunctive test to cytogenetics. This experience demonstrates that FISH can provide a rapid and accurate clinical method for prenatal identification of chromosome aneuploidies.\n" ], "offsets": [ [ 0, 1978 ] ] } ]

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[ { "id": "8328452__text", "type": "abstract", "text": [ "Molecular analysis of Hurler syndrome in Druze and Muslim Arab patients in Israel: multiple allelic mutations of the IDUA gene in a small geographic area. The mutations underlying Hurler syndrome (mucopolysaccharidosis IH) in Druze and Muslim Israeli Arab patients have been characterized. Four alleles were identified, using a combination of (a) PCR amplification of reverse-transcribed RNA or genomic DNA segments, (b) cycle sequencing of PCR products, and (c) restriction-enzyme analysis. One allele has two amino acid substitutions, Gly409-->Arg in exon 9 and Ter-->Cys in exon 14. The other three alleles have mutations in exon 2 (Tyr64-->Ter), exon 7 (Gln310-->Ter), or exon 8 (Thr366-->Pro). Transfection of mutagenized cDNAs into Cos-1 cells showed that two missense mutations, Thr366-->Pro and Ter-->Cys, permitted the expression of only trace amounts of alpha-L-iduronidase activity, whereas Gly409-->Arg permitted the expression of 60% as much enzyme as did the normal cDNA. The nonsense mutations were associated with abnormalities of RNA processing: (1) both a very low level of mRNA and skipping of exon 2 for Tyr64-->Ter and (2) utilization of a cryptic splice site for Gln310-->Ter. In all instances, the probands were found homozygous, and the parents heterozygous, for the mutant alleles, as anticipated from the consanguinity in each family. The two-mutation allele was identified in a family from Gaza; the other three alleles were found in seven families, five of them Druze, residing in a very small area of northern Israel. Since such clustering suggests a classic founder effect, the presence of three mutant alleles of the IDUA gene was unexpected.\n" ], "offsets": [ [ 0, 1674 ] ] } ]

[ { "id": "8328452_T1", "type": "Gene", "text": [ "IDUA" ], "offsets": [ [ 117, 121 ] ], "normalized": [] }, { "id": "8328452_T2", "type": "SNP", "text": [ "Gly409-->Arg" ], "offsets": [ [ 537, 549 ] ], "normalized": [] }, { "id": "8328452_T4", "type": "SNP", "text": [ "Tyr64-->Ter" ], "offsets": [ [ 636, 647 ] ], "normalized": [] }, { "id": "8328452_T5", "type": "SNP", "text": [ "Gln310-->Ter" ], "offsets": [ [ 658, 670 ] ], "normalized": [] }, { "id": "8328452_T6", "type": "SNP", "text": [ "Thr366-->Pro" ], "offsets": [ [ 684, 696 ] ], "normalized": [] }, { "id": "8328452_T7", "type": "SNP", "text": [ "Thr366-->Pro" ], "offsets": [ [ 786, 798 ] ], "normalized": [] }, { "id": "8328452_T9", "type": "SNP", "text": [ "Gly409-->Arg" ], "offsets": [ [ 902, 914 ] ], "normalized": [] }, { "id": "8328452_T10", "type": "SNP", "text": [ "Tyr64-->Ter" ], "offsets": [ [ 1124, 1135 ] ], "normalized": [] }, { "id": "8328452_T11", "type": "SNP", "text": [ "Gln310-->Ter" ], "offsets": [ [ 1185, 1197 ] ], "normalized": [] }, { "id": "8328452_T12", "type": "Gene", "text": [ "IDUA" ], "offsets": [ [ 1648, 1652 ] ], "normalized": [] } ]

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[ { "id": "8328452_R1", "type": "AssociatedTo", "arg1_id": "8328452_T2", "arg2_id": "8328452_T1", "normalized": [] }, { "id": "8328452_R3", "type": "AssociatedTo", "arg1_id": "8328452_T4", "arg2_id": "8328452_T1", "normalized": [] }, { "id": "8328452_R4", "type": "AssociatedTo", "arg1_id": "8328452_T5", "arg2_id": "8328452_T1", "normalized": [] }, { "id": "8328452_R5", "type": "AssociatedTo", "arg1_id": "8328452_T6", "arg2_id": "8328452_T1", "normalized": [] }, { "id": "8328452_R6", "type": "AssociatedTo", "arg1_id": "8328452_T9", "arg2_id": "8328452_T12", "normalized": [] }, { "id": "8328452_R7", "type": "AssociatedTo", "arg1_id": "8328452_T10", "arg2_id": "8328452_T12", "normalized": [] }, { "id": "8328452_R8", "type": "AssociatedTo", "arg1_id": "8328452_T11", "arg2_id": "8328452_T12", "normalized": [] } ]

[ { "id": "8328456__text", "type": "abstract", "text": [ "Anticipation in bipolar affective disorder. Anticipation refers to the increase in disease severity or decrease in age at onset in succeeding generations. This phenomenon, formerly ascribed to observation biases, correlates with the expansion of trinucleotide repeat sequences (TNRs) in some disorders. If present in bipolar affective disorder (BPAD), anticipation could provide clues to its genetic etiology. We compared age at onset and disease severity between two generations of 34 unilineal families ascertained for a genetic linkage study of BPAD. Life-table analyses showed a significant decrease in survival to first mania or depression from the first to the second generation (P < .001). Intergenerational pairwise comparisons showed both a significantly earlier age at onset (P < .001) and a significantly increased disease severity (P < .001) in the second generation. This difference was significant under each of four data-sampling schemes which excluded probands in the second generation. The second generation experienced onset 8.9-13.5 years earlier and illness 1.8-3.4 times more severe than did the first generation. In additional analyses, drug abuse, deaths of affected individuals prior to interview, decreased fertility, censoring of age at onset, and the cohort effect did not affect our results. We conclude that genetic anticipation occurs in this sample of unilineal BPAD families. These findings may implicate genes with expanding TNRs in the genetic etiology of BPAD.\n" ], "offsets": [ [ 0, 1496 ] ] } ]

[ { "id": "8328456_T1", "type": "Gene", "text": [ "BPAD" ], "offsets": [ [ 345, 349 ] ], "normalized": [] }, { "id": "8328456_T2", "type": "Gene", "text": [ "BPAD" ], "offsets": [ [ 548, 552 ] ], "normalized": [] }, { "id": "8328456_T3", "type": "Gene", "text": [ "BPAD" ], "offsets": [ [ 1393, 1397 ] ], "normalized": [] }, { "id": "8328456_T4", "type": "Gene", "text": [ "BPAD" ], "offsets": [ [ 1490, 1494 ] ], "normalized": [] } ]

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[ { "id": "8434605__text", "type": "abstract", "text": [ "Identification of individuals by analysis of biallelic DNA markers, using PCR and solid-phase minisequencing. We have developed a new method for forensic identification of individuals, in which a panel of biallelic DNA markers are amplified by the PCR, and the variable nucleotides are detected in the amplified DNA fragments by the solid-phase minisequencing method. A panel of 12 common polymorphic nucleotides located on different chromosomes with reported allele frequencies close to .5 were chosen for the test. The allele frequencies for most of the markers were found to be similar in the Finnish and other Caucasian populations. We also introduce a novel approach for rapid determination of the population frequencies of biallelic markers. By this approach we were able to determine the allele frequencies of the markers in the Finnish population, by quantitative analysis of three pooled DNA samples representing 3,000 individuals. The power of discrimination and exclusion of the solid-phase minisequencing typing test with 12 markers was similar to that of three VNTR markers that are routinely used in forensic analyses at our institute. The solid-phase minisequencing method was successfully applied to type paternity and forensic case samples. We also show that the quantitative nature of our method allows typing of mixed samples.\n" ], "offsets": [ [ 0, 1346 ] ] } ]

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[ { "id": "8488834__text", "type": "abstract", "text": [ "Insurance commissioners and genetic discrimination.\n" ], "offsets": [ [ 0, 52 ] ] } ]

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[ { "id": "7902670__text", "type": "abstract", "text": [ "Homozygotes for the autosomal dominant neoplasia syndrome (MEN1). Families in which both parents are heterozygotes for the same autosomal dominant neoplasia syndrome are extremely unusual. Recently, we had the unique opportunity to evaluate three symptomatic siblings from the union between two unrelated individuals affected by multiple endocrine neoplasia type 1 (MEN1). When the three siblings and their parents and relatives were genotyped for 12 markers tightly linked to the MEN1 locus, at 11q13, two of the siblings were found to be homozygotes, and one a heterozygote, for MEN1. With regard to the MEN1 syndrome, no phenotypic differences were observed between the two homozygotes and the heterozygotes. However, the two homozygotes showed unexplained infertility, which was not the case for any of the heterozygotes. Thus, MEN1 appears to be a disease with complete dominance, and the presence of two MEN1 alleles with mutations of the type that occur constitutionally may be insufficient for tumor development.\n" ], "offsets": [ [ 0, 1021 ] ] } ]

[ { "id": "7902670_T1", "type": "Gene", "text": [ "MEN1" ], "offsets": [ [ 59, 63 ] ], "normalized": [] }, { "id": "7902670_T2", "type": "Gene", "text": [ "MEN1" ], "offsets": [ [ 366, 370 ] ], "normalized": [] }, { "id": "7902670_T3", "type": "Gene", "text": [ "MEN1" ], "offsets": [ [ 481, 485 ] ], "normalized": [] }, { "id": "7902670_T4", "type": "Gene", "text": [ "MEN1" ], "offsets": [ [ 581, 585 ] ], "normalized": [] }, { "id": "7902670_T5", "type": "Gene", "text": [ "MEN1" ], "offsets": [ [ 606, 610 ] ], "normalized": [] }, { "id": "7902670_T6", "type": "Gene", "text": [ "MEN1" ], "offsets": [ [ 832, 836 ] ], "normalized": [] }, { "id": "7902670_T7", "type": "Gene", "text": [ "MEN1" ], "offsets": [ [ 910, 914 ] ], "normalized": [] } ]

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[ { "id": "8387722__text", "type": "abstract", "text": [ "A base substitution in the promoter associated with the human haptoglobin 2-1 modified phenotype decreases transcriptional activity and responsiveness to interleukin-6 in human hepatoma cells. An A-to-C base substitution at nucleotide position -61 in the promoter region of the human haptoglobin gene (Hp) has been shown to be strongly associated with the haptoglobin 2-1 modified (Hp2-1mod) phenotype. In order to investigate whether this base substitution is the cause of reduced expression of the Hp2 allele relative to the Hp1 allele in individuals with the Hp2-1mod phenotype, we used the chloramphenicol acetyl transferase (CAT) expression system to evaluate promoter function. In HepG2 cells, which normally express their endogenous haptoglobin genes, CAT plasmid constructs with the -61C base change in the promoter had about 10-fold-lower transcriptional activity after transfection than did the Hp control construct. The -61C substitution also rendered the construct unresponsive to treatment by interleukin-6 after transfection into Hep3B2 cells, which normally do not express haptoglobin but do so in response to stimulation by acute-phase reactants. In addition, two base substitutions, T to A and A to G, at positions -104 and -55G, respectively, in the promoter region of the Hp1 allele, are also associated with the Hp2-1mod phenotype. CAT constructs with both substitutions (-104A-55G) and with one substitution (-55G) showed activity similar to that in the Hp control when transfected into both HepG2 and Hep3B2 cells, although interleukin-6 induction was less than with the Hp control construct. These results further support the hypothesis that the Hp2-1mod phenotype results, in part, from the -61C mutation in the promoter region of the Hp2 gene.\n" ], "offsets": [ [ 0, 1769 ] ] } ]

[ { "id": "8387722_T1", "type": "Gene", "text": [ "haptoglobin" ], "offsets": [ [ 284, 295 ] ], "normalized": [] }, { "id": "8387722_T2", "type": "Gene", "text": [ "Hp" ], "offsets": [ [ 302, 304 ] ], "normalized": [] }, { "id": "8387722_T3", "type": "Gene", "text": [ "haptoglobin 2-1" ], "offsets": [ [ 62, 77 ] ], "normalized": [] }, { "id": "8387722_T4", "type": "SNP", "text": [ "A-to-C base substitution at nucleotide position -61" ], "offsets": [ [ 196, 247 ] ], "normalized": [] }, { "id": "8387722_T5", "type": "Gene", "text": [ "haptoglobin 2-1" ], "offsets": [ [ 356, 371 ] ], "normalized": [] }, { "id": "8387722_T6", "type": "Gene", "text": [ "Hp2" ], "offsets": [ [ 500, 503 ] ], "normalized": [] }, { "id": "8387722_T7", "type": "Gene", "text": [ "Hp1" ], "offsets": [ [ 527, 530 ] ], "normalized": [] }, { "id": "8387722_T8", "type": "SNP", "text": [ "T to A and A to G, at positions -104 and -55G, respectively" ], "offsets": [ [ 1200, 1259 ] ], "normalized": [] }, { "id": "8387722_T9", "type": "Gene", "text": [ "Hp1" ], "offsets": [ [ 1291, 1294 ] ], "normalized": [] }, { "id": "8387722_T10", "type": "Gene", "text": [ "Hp2" ], "offsets": [ [ 1759, 1762 ] ], "normalized": [] }, { "id": "8387722_T11", "type": "Gene", "text": [ "interleukin-6" ], "offsets": [ [ 154, 167 ] ], "normalized": [] }, { "id": "8387722_T12", "type": "SNP", "text": [ "-104A-55G" ], "offsets": [ [ 1392, 1401 ] ], "normalized": [] }, { "id": "8387722_T13", "type": "Gene", "text": [ "interleukin-6" ], "offsets": [ [ 1546, 1559 ] ], "normalized": [] } ]

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[ { "id": "8387722_R1", "type": "Equals", "arg1_id": "8387722_T1", "arg2_id": "8387722_T2", "normalized": [] }, { "id": "8387722_R2", "type": "AssociatedTo", "arg1_id": "8387722_T4", "arg2_id": "8387722_T1", "normalized": [] }, { "id": "8387722_R3", "type": "AssociatedTo", "arg1_id": "8387722_T8", "arg2_id": "8387722_T9", "normalized": [] } ]

[ { "id": "8328462__text", "type": "abstract", "text": [ "beta-Hexosaminidase isozymes from cells cotransfected with alpha and beta cDNA constructs: analysis of the alpha-subunit missense mutation associated with the adult form of Tay-Sachs disease. In vitro mutagenesis and transient expression in COS cells has been used to associate a missense mutation with a clinical or biochemical phenotype. Mutations affecting the alpha-subunit of beta-hexosaminidase A (alpha beta) (E.C.3.2.1.52) result in Tay-Sachs disease. Because hexosaminidase A is heterodimeric, analysis of alpha-chain mutations is not straightforward. We examine three approaches utilizing previously identified mutations affecting alpha-chain folding. These involve transfection of (1) the alpha cDNA alone; (2) a beta cDNA construct encoding a beta-subunit substituted at a position homologous to that of the alpha-subunit, and (3) both alpha and beta cDNAs. The latter two procedures amplified residual activity levels over that of patient samples, an effect not previously found with mutations affecting an \"active\" alpha Arg residue. This effect may help to discriminate between protein-folding and active-site mutations. We conclude that, with proper controls, the latter method of cotransfection can be used to evaluate the effects and perhaps to predict the clinical course of some alpha-chain mutations. Using this technique, we demonstrate that the adult-onset Tay-Sachs mutation, alpha Gly --> Ser269, does not directly affect alpha beta dimerization but exerts an indirect effect on the dimer through destabilizing the folded alpha-subunit at physiological temperatures. Two other alpha mutations linked to more severe phenotypes appear to inhibit the initial folding of the subunit.\n" ], "offsets": [ [ 0, 1705 ] ] } ]

[ { "id": "8328462_T1", "type": "Gene", "text": [ "beta-Hexosaminidase" ], "offsets": [ [ 0, 19 ] ], "normalized": [] }, { "id": "8328462_T2", "type": "Gene", "text": [ "beta-hexosaminidase A" ], "offsets": [ [ 381, 402 ] ], "normalized": [] }, { "id": "8328462_T3", "type": "Gene", "text": [ "hexosaminidase A" ], "offsets": [ [ 468, 484 ] ], "normalized": [] }, { "id": "8328462_T4", "type": "SNP", "text": [ "Gly --> Ser269" ], "offsets": [ [ 1406, 1420 ] ], "normalized": [] } ]

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[ { "id": "8503442__text", "type": "abstract", "text": [ "The haplotype-relative-risk (HRR) method for analysis of association in nuclear families. One major problem in studying an association between a marker locus and a disease is the selection of an appropriate group of controls. However, this problem of population stratification can be circumvented in a quite elegant manner by family-based methods. The haplotype-relative-risk (HRR) method, which samples nuclear families with a single affected child and uses the parental haplotypes not transmitted to that child as a control individual, represents such a method for estimating the relative risk of a marker phenotype. In the special case of a recessive disease, it was already known that the equivalence of the HRR method with the classical relative risk (RR) obtained from independent samples holds only if the probability theta of a recombination between marker and disease locus is zero. We extend this result to an arbitrary mode of inheritance. Furthermore, we compare the distribution of the estimators for HRR and RR and show that, in the case of a positive linkage disequilibrium between a marker and disease allele, the distribution of the estimator for HRR is (stochastically) smaller than that for RR, irrespective of the recombination fraction. The practical implication of this result is that, for the HRR method, there is no tendency to give unduly high risk estimators, even for theta > 0. Finally, we give an expression for the standard error of the estimator for HRR by taking into account the nonindependence of transmitted and nontransmitted parental marker alleles in the case of theta > 0.\n" ], "offsets": [ [ 0, 1612 ] ] } ]

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[ { "id": "9042931__text", "type": "abstract", "text": [ "Detecting disease-predisposing variants: the haplotype method. For many HLA-associated diseases, multiple alleles-- and, in some cases, multiple loci--have been suggested as the causative agents. The haplotype method for identifying disease-predisposing amino acids in a genetic region is a stratification analysis. We show that, for each haplotype combination containing all the amino acid sites involved in the disease process, the relative frequencies of amino acid variants at sites not involved in disease but in linkage disequilibrium with the disease-predisposing sites are expected to be the same in patients and controls. The haplotype method is robust to mode of inheritance and penetrance of the disease and can be used to determine unequivocally whether all amino acid sites involved in the disease have not been identified. Using a resampling technique, we developed a statistical test that takes account of the nonindependence of the sites sampled. Further, when multiple sites in the genetic region are involved in disease, the test statistic gives a closer fit to the null expectation when some--compared with none--of the true predisposing factors are included in the haplotype analysis. Although the haplotype method cannot distinguish between very highly correlated sites in one population, ethnic comparisons may help identify the true predisposing factors. The haplotype method was applied to insulin-dependent diabetes mellitus (IDDM) HLA class II DQA1-DQB1 data from Caucasian, African, and Japanese populations. Our results indicate that the combination DQA1#52 (Arg predisposing) DQB1#57 (Asp protective), which has been proposed as an important IDDM agent, does not include all the predisposing elements. With rheumatoid arthritis HLA class II DRB1 data, the results were consistent with the shared-epitope hypothesis.\n" ], "offsets": [ [ 0, 1845 ] ] } ]

[ { "id": "9042931_T1", "type": "Gene", "text": [ "DRB1" ], "offsets": [ [ 1770, 1774 ] ], "normalized": [] }, { "id": "9042931_T2", "type": "Gene", "text": [ "DQA1#52" ], "offsets": [ [ 1578, 1585 ] ], "normalized": [] }, { "id": "9042931_T3", "type": "Gene", "text": [ "DQB1#57" ], "offsets": [ [ 1605, 1612 ] ], "normalized": [] } ]

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[ { "id": "8981970__text", "type": "abstract", "text": [ "Expression of DAZ, an azoospermia factor candidate, in human spermatogonia.\n" ], "offsets": [ [ 0, 76 ] ] } ]

[ { "id": "8981970_T1", "type": "Gene", "text": [ "DAZ" ], "offsets": [ [ 14, 17 ] ], "normalized": [] } ]

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[ { "id": "9245996__text", "type": "abstract", "text": [ "The seventh form of autosomal recessive limb-girdle muscular dystrophy is mapped to 17q11-12. The group of autosomal recessive (AR) muscular dystrophies includes, among others, two main clinical entities, the limb-girdle muscular dystrophies (LGMDs) and the distal muscular dystrophies. The former are characterized mainly by muscle wasting of the upper and lower limbs, with a wide range of clinical severity. This clinical heterogeneity has been demonstrated at the molecular level, since the genes for six AR forms have been cloned and/or have been mapped to 15q15.1 (LGMD2A), 2p12-16 (LGMD2B), 13q12 (LGMD2C), 17q12-q21.33 (LGMD2D),4q12 (LGMD2E), and 5q33-34 (LGMD2F). The AR distal muscular dystrophies originally included two subgroups, Miyoshi myopathy, characterized mainly by extremely elevated serum creatine kinase (CK) activity and by a dystrophic muscle pattern, and Nonaka myopathy, which is distinct from the others because of the normal to slightly elevated serum CK levels and a myopathic muscle pattern with rimmed vacuoles. With regard to our unclassified AR LGMD families, analysis of the affected sibs from one of them (family LG61) revealed some clinical and laboratory findings (early involvement of the distal muscles, mildly elevated serum CK levels, and rimmed vacuoles in muscle biopsies) that usually are not observed in the analysis of patients with LGMD2A-LGMD2F. In the present investigation, through a genomewide search in family LG61, we demonstrated linkage of the allele causing this form of muscular dystrophy to a 3-cM region on 17q11-12. We suggest that this form, which, interestingly, clinically resembles AR Kugelberg-Welander disease, should be classified as LGMD2G. In addition, our results indicate the existence of still another locus causing severe LGMD.\n" ], "offsets": [ [ 0, 1801 ] ] } ]

[ { "id": "9245996_T1", "type": "Gene", "text": [ "(LGMD2A)," ], "offsets": [ [ 570, 579 ] ], "normalized": [] }, { "id": "9245996_T2", "type": "Gene", "text": [ "(LGMD2B)," ], "offsets": [ [ 588, 597 ] ], "normalized": [] }, { "id": "9245996_T3", "type": "Gene", "text": [ "(LGMD2C)," ], "offsets": [ [ 604, 613 ] ], "normalized": [] }, { "id": "9245996_T4", "type": "Gene", "text": [ "(LGMD2D),4q12" ], "offsets": [ [ 627, 640 ] ], "normalized": [] }, { "id": "9245996_T5", "type": "Gene", "text": [ "(LGMD2E)," ], "offsets": [ [ 641, 650 ] ], "normalized": [] }, { "id": "9245996_T6", "type": "Gene", "text": [ "(LGMD2F)." ], "offsets": [ [ 663, 672 ] ], "normalized": [] }, { "id": "9245996_T7", "type": "Gene", "text": [ "LGMD2G." ], "offsets": [ [ 1701, 1708 ] ], "normalized": [] } ]

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[ { "id": "9311748__text", "type": "abstract", "text": [ "Accurate inference of relationships in sib-pair linkage studies. Relative-pair designs are routinely employed in linkage studies of complex genetic diseases and quantitative traits. Valid application of these methods requires correct specification of the relationships of the pairs. For example, within a sibship, presumed full sibs actually might be MZ twins, half sibs, or unrelated. Misclassification of half-sib pairs or unrelated individuals as full sibs can result in reduced power to detect linkage. When other family members, such as parents or additional siblings, are available, incorrectly specified relationships usually will be detected through apparent incompatibilities with Mendelian inheritance. Without other family members, sibling relationships cannot be determined absolutely, but they still can be inferred probabilistically if sufficient genetic marker data are available. In this paper, we describe a simple likelihood ratio method to infer the true relationship of a putative sibling pair. We explore the number of markers required to accurately infer relationships typically encountered in a sib-pair study, as a function of marker allele frequencies, marker spacing, and genotyping error rate, and we conclude that very accurate inference of relationships can be achieved, given the marker data from even part of a genome scan. We compare our method to related methods of relationship inference that have been suggested. Finally, we demonstrate the value of excluding non-full sibs in a genetic linkage study of non-insulin-dependent diabetes mellitus.\n" ], "offsets": [ [ 0, 1580 ] ] } ]

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[ { "id": "9399915__text", "type": "abstract", "text": [ "Centromere DNA dynamics: latent centromeres and neocentromere formation.\n" ], "offsets": [ [ 0, 73 ] ] } ]

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[ { "id": "8981950__text", "type": "abstract", "text": [ "Hereditary multiple exostoses (EXT): mutational studies of familial EXT1 cases and EXT-associated malignancies. Hereditary multiple exostoses (EXT) is an autosomal dominant disorder characterized by the formation of cartilage-capped prominences that develop from the growth centers of the long bones. EXT is genetically heterogeneous, with three loci, currently identified on chromosomes 8q24.1, 11p13, and 19q. The EXT1 gene, located on chromosome 8q24.1, has been cloned and is encoded by a 3.4-kb cDNA. Five mutations in the EXT1 gene have been identified--four germ-line mutations, including two unrelated families with the same mutation, and one somatic mutation in a patient with chondrosarcoma. Four of the mutations identified resulted in frameshifts and premature termination codons, while the fifth mutation resulted in a substitution of leucine for arginine. Loss of heterozygosity (LOH) analysis of chondrosarcomas and chondroblastomas revealed multiple LOH events at loci on chromosomes 3q, 8q, 10q, and 19q. One sporadic chondrosarcoma demonstrated LOH for EXT1 and EXT3, while a second underwent LOH for EXT2 and chromosome 10. A third chondrosarcoma underwent LOH for EXT1 and chromosome 3q. These results agree with previous findings that mutations at EXT1 and multiple genetic events that include LOH at other loci may be required for the development of chondrosarcoma.\n" ], "offsets": [ [ 0, 1388 ] ] } ]

[ { "id": "8981950_T1", "type": "Gene", "text": [ "EXT1" ], "offsets": [ [ 416, 420 ] ], "normalized": [] }, { "id": "8981950_T2", "type": "Gene", "text": [ "EXT1" ], "offsets": [ [ 528, 532 ] ], "normalized": [] }, { "id": "8981950_T3", "type": "Gene", "text": [ "EXT1" ], "offsets": [ [ 1071, 1075 ] ], "normalized": [] }, { "id": "8981950_T4", "type": "Gene", "text": [ "EXT3" ], "offsets": [ [ 1080, 1084 ] ], "normalized": [] }, { "id": "8981950_T5", "type": "Gene", "text": [ "EXT2" ], "offsets": [ [ 1119, 1123 ] ], "normalized": [] }, { "id": "8981950_T6", "type": "Gene", "text": [ "EXT1" ], "offsets": [ [ 1184, 1188 ] ], "normalized": [] }, { "id": "8981950_T7", "type": "Gene", "text": [ "EXT1" ], "offsets": [ [ 1269, 1273 ] ], "normalized": [] } ]

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[ { "id": "9199562__text", "type": "abstract", "text": [ "Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMNT and SMNC gene copy number. The survival motor neuron (SMN) transcript is encoded by two genes, SMNT and SMNC. The autosomal recessive proximal spinal muscular atrophy that maps to 5q12 is caused by mutations in the SMNT gene. The SMNT gene can be distinguished from the SMNC gene by base-pair changes in exons 7 and 8. SMNT exon 7 is not detected in approximately 95% of SMA cases due to either deletion or sequence-conversion events. Small mutations in SMNT now have been identified in some of the remaining nondeletion patients. However, there is no reliable quantitative assay for SMNT, to distinguish SMA compound heterozygotes from non-5q SMA-like cases (phenocopies) and to accurately determine carrier status. We have developed a quantitative PCR assay for the determination of SMNT and SMNC gene-copy number. This report demonstrates how risk estimates for the diagnosis and detection of SMA carriers can be modified by the accurate determination of SMNT copy number.\n" ], "offsets": [ [ 0, 1069 ] ] } ]

[ { "id": "9199562_T1", "type": "Gene", "text": [ "SMNT" ], "offsets": [ [ 88, 92 ] ], "normalized": [] }, { "id": "9199562_T2", "type": "Gene", "text": [ "SMNC" ], "offsets": [ [ 97, 101 ] ], "normalized": [] }, { "id": "9199562_T3", "type": "Gene", "text": [ "SMNT" ], "offsets": [ [ 188, 192 ] ], "normalized": [] }, { "id": "9199562_T4", "type": "Gene", "text": [ "SMNC." ], "offsets": [ [ 197, 202 ] ], "normalized": [] }, { "id": "9199562_T5", "type": "Gene", "text": [ "SMNT" ], "offsets": [ [ 308, 312 ] ], "normalized": [] }, { "id": "9199562_T6", "type": "Gene", "text": [ "SMNT" ], "offsets": [ [ 323, 327 ] ], "normalized": [] }, { "id": "9199562_T7", "type": "Gene", "text": [ "SMNC" ], "offsets": [ [ 363, 367 ] ], "normalized": [] }, { "id": "9199562_T8", "type": "Gene", "text": [ "SMNT" ], "offsets": [ [ 412, 416 ] ], "normalized": [] }, { "id": "9199562_T9", "type": "Gene", "text": [ "SMNT" ], "offsets": [ [ 547, 551 ] ], "normalized": [] }, { "id": "9199562_T10", "type": "Gene", "text": [ "SMNT," ], "offsets": [ [ 677, 682 ] ], "normalized": [] }, { "id": "9199562_T11", "type": "Gene", "text": [ "SMNT" ], "offsets": [ [ 878, 882 ] ], "normalized": [] }, { "id": "9199562_T12", "type": "Gene", "text": [ "SMNC" ], "offsets": [ [ 887, 891 ] ], "normalized": [] }, { "id": "9199562_T13", "type": "Gene", "text": [ "SMNT" ], "offsets": [ [ 1051, 1055 ] ], "normalized": [] } ]

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[ { "id": "9042937__text", "type": "abstract", "text": [ "HLA sharing and history of miscarriage among women with rheumatoid arthritis.\n" ], "offsets": [ [ 0, 78 ] ] } ]

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[ { "id": "9399882__text", "type": "abstract", "text": [ "Inherited interstitial duplications of proximal 15q: genotype-phenotype correlations. We present the cytogenetic, molecular cytogenetic, and molecular genetic results on 20 unrelated patients with an interstitial duplication of the proximal long arm of chromosome 15. Multiple probes showed that the Prader-Willi/Angelman critical region (PWACR) was included in the duplication in 4/20 patients, each ascertained with developmental delay. The duplication was also found in two affected but not in three unaffected sibs of one of these patients. All four probands had inherited their duplication from their mothers, three of whom were also affected. Two of the affected mothers also carried a maternally inherited duplication, whereas the duplication in the unaffected mother and in an unaffected grandmother was paternal in origin, raising the possibility of a parental-origin effect. The PWACR was not duplicated in the remaining 16 patients, of whom 4 were referred with developmental delay. In the 14 families for which parental samples were available, the duplication was inherited with equal frequency from a phenotypically normal parent, mother or father. Comparative genomic hybridization undertaken on two patients suggested that proximal 15q outside the PWACR was the origin of the duplicated material. The use of PWACR probes discriminates between a large group of duplications of no apparent clinical significance and a smaller group, in which a maternally derived PWACR duplication is consistently associated with developmental delay and speech difficulties but not with overt features of either Prader-Willi syndrome or Angelman syndrome.\n" ], "offsets": [ [ 0, 1652 ] ] } ]

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[ { "id": "9326327__text", "type": "abstract", "text": [ "Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients. Velo-cardio-facial syndrome (VCFS) is a relatively common developmental disorder characterized by craniofacial anomalies and conotruncal heart defects. Many VCFS patients have hemizygous deletions for a part of 22q11, suggesting that haploinsufficiency in this region is responsible for its etiology. Because most cases of VCFS are sporadic, portions of 22q11 may be prone to rearrangement. To understand the molecular basis for chromosomal deletions, we defined the extent of the deletion, by genotyping 151 VCFS patients and performing haplotype analysis on 105, using 15 consecutive polymorphic markers in 22q11. We found that 83% had a deletion and >90% of these had a similar approximately 3 Mb deletion, suggesting that sequences flanking the common breakpoints are susceptible to rearrangement. We found no correlation between the presence or size of the deletion and the phenotype. To further define the chromosomal breakpoints among the VCFS patients, we developed somatic hybrid cell lines from a set of VCFS patients. An 11-kb resolution physical map of a 1,080-kb region that includes deletion breakpoints was constructed, incorporating genes and expressed sequence tags (ESTs) isolated by the hybridization selection method. The ordered markers were used to examine the two separated copies of chromosome 22 in the somatic hybrid cell lines. In some cases, we were able to map the chromosome breakpoints within a single cosmid. A 480-kb critical region for VCFS has been delineated, including the genes for GSCL, CTP, CLTD, HIRA, and TMVCF, as well as a number of novel ordered ESTs.\n" ], "offsets": [ [ 0, 1682 ] ] } ]

[ { "id": "9326327_T1", "type": "Gene", "text": [ "GSCL," ], "offsets": [ [ 1605, 1610 ] ], "normalized": [] }, { "id": "9326327_T2", "type": "Gene", "text": [ "CTP," ], "offsets": [ [ 1611, 1615 ] ], "normalized": [] }, { "id": "9326327_T3", "type": "Gene", "text": [ "CLTD," ], "offsets": [ [ 1616, 1621 ] ], "normalized": [] }, { "id": "9326327_T4", "type": "Gene", "text": [ "HIRA," ], "offsets": [ [ 1622, 1627 ] ], "normalized": [] }, { "id": "9326327_T5", "type": "Gene", "text": [ "TMVCF," ], "offsets": [ [ 1632, 1638 ] ], "normalized": [] } ]

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[ { "id": "9042906__text", "type": "abstract", "text": [ "Congenital anomalies and childhood cancer in Great Britain. The presence of cancer and a congenital anomaly in the same child may be explained in certain cases by an underlying genetic abnormality. The study of these associations may lead to the identification of genes that are important in both processes. We have examined the records of 20,304 children with cancer in Britain, who were entered into the National Registry of Childhood Tumors (NRCT) during 1971-86, for the presence of congenital anomalies. The frequency of anomalies was much higher among children with solid tumors (4.4%) than among those with leukemia or lymphoma (2.6%; P < .0001). The types of cancer with the highest rates of anomalies were Wilms tumor (8.1%), Ewing sarcoma (5.8%), hepatoblastoma (6.4%), and gonadal and germ-cell tumors (6.4%). Cases of spina bifida and abnormalities of the eye, ribs, and spine were more common in children with cancer than among population-based controls. Future studies may be directed toward identifying the developmental pathways and the relevant genes that are involved in the overlap between pediatric cancer and malformation.\n" ], "offsets": [ [ 0, 1144 ] ] } ]

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[ { "id": "11644969__text", "type": "abstract", "text": [ "Ethical guidelines for enzyme therapy in neuronopathic Gaucher disease.\n" ], "offsets": [ [ 0, 72 ] ] } ]

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[ { "id": "9326328__text", "type": "abstract", "text": [ "Identification of a locus for progressive familial intrahepatic cholestasis PFIC2 on chromosome 2q24. Progressive familial intrahepatic cholestasis (PFIC; OMIM 211600) is the second most common familial cholestatic syndrome presenting in infancy. A locus has previously been mapped to chromosome 18q21-22 in the original Byler pedigree. This chromosomal region also harbors the locus for benign recurrent intrahepatic cholestasis (BRIC) a related phenotype. Linkage analysis in six consanguineous PFIC pedigrees from the Middle East has previously excluded linkage to chromosome 18q21-22, indicating the existence of locus heterogeneity within the PFIC phenotype. By use of homozygosity mapping and a genome scan in these pedigrees, a locus designated \"PFIC2\" has been mapped to chromosome 2q24. A maximum LOD score of 8.5 was obtained in the interval between marker loci D2S306 and D2S124, with all families linked.\n" ], "offsets": [ [ 0, 917 ] ] } ]

[ { "id": "9326328_T1", "type": "Gene", "text": [ "PFIC2" ], "offsets": [ [ 76, 81 ] ], "normalized": [] }, { "id": "9326328_T2", "type": "Gene", "text": [ "PFIC" ], "offsets": [ [ 497, 501 ] ], "normalized": [] }, { "id": "9326328_T3", "type": "Gene", "text": [ "PFIC" ], "offsets": [ [ 648, 652 ] ], "normalized": [] }, { "id": "9326328_T4", "type": "Gene", "text": [ "\"PFIC2\"" ], "offsets": [ [ 752, 759 ] ], "normalized": [] } ]

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[ { "id": "8981969__text", "type": "abstract", "text": [ "Prevalence and parental origin of de novo RET mutations in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma. Le Groupe d'Etude des Tumeurs a Calcitonine.\n" ], "offsets": [ [ 0, 183 ] ] } ]

[ { "id": "8981969_T1", "type": "Gene", "text": [ "RET" ], "offsets": [ [ 42, 45 ] ], "normalized": [] } ]

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[ { "id": "9150164__text", "type": "abstract", "text": [ "A gene for autosomal dominant nonsyndromic hearing loss (DFNA12) maps to chromosome 11q22-24. We performed linkage analysis in a Belgian family with autosomal dominant midfrequency hearing loss, which has a prelingual onset and a nonprogressive course in most patients. We found LOD scores >6 with markers on chromosome 11q. Analysis of key recombinants maps this deafness gene (DFNA12) to a 36-cM interval on chromosome 11q22-24, between markers D11S4120 and D11S912. The critical regions for the recessive deafness locus DFNB2 and the dominant locus DFNA11, which were previously localized to the long arm of chromosome 11, do not overlap with the candidate interval of DFNA12.\n" ], "offsets": [ [ 0, 680 ] ] } ]

[ { "id": "9150164_T1", "type": "Gene", "text": [ "(DFNA12)" ], "offsets": [ [ 378, 386 ] ], "normalized": [] }, { "id": "9150164_T2", "type": "Gene", "text": [ "DFNB2" ], "offsets": [ [ 523, 528 ] ], "normalized": [] }, { "id": "9150164_T3", "type": "Gene", "text": [ "DFNA11," ], "offsets": [ [ 552, 559 ] ], "normalized": [] }, { "id": "9150164_T4", "type": "Gene", "text": [ "DFNA12." ], "offsets": [ [ 672, 679 ] ], "normalized": [] } ]

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[ { "id": "9326322__text", "type": "abstract", "text": [ "Analysis of the RPGR gene in 11 pedigrees with the retinitis pigmentosa type 3 genotype: paucity of mutations in the coding region but splice defects in two families. X-linked retinitis pigmentosa (XLRP) is a severe form of inherited progressive retinal degeneration. The RP3 (retinitis pigmentosa type 3) locus at Xp21.1 is believed to account for the disease in the majority of XLRP families. Linkage analysis and identification of patients with chromosomal deletion have refined the location of the RP3 locus and recently have led to the cloning of the RPGR (retinitis pigmentosa GTPase regulator) gene, which has been shown to be mutated in 10%-15% of XLRP patients. In order to systematically characterize the RPGR mutations, we identified 11 retinitis pigmentosa type III (RP3) families by haplotype analysis. Sequence analysis of the PCR-amplified genomic DNA from patients representing these RP3 families did not reveal any causative mutation in RPGR exons 2-19, spanning >98% of the coding region. In patients from two families, we identified transition mutations in the intron region near splice sites (IVS10+3 and IVS13-8). RNA analysis showed that both splice-site mutations resulted in the generation of aberrant RPGR transcripts. Our results support the hypothesis that mutations in the reported RPGR gene are not a common defect in the RP3 subtype of XLRP and that a majority of causative mutations may reside either in as yet unidentified RPGR exons or in another nearby gene at Xp21.1.\n" ], "offsets": [ [ 0, 1503 ] ] } ]

[ { "id": "9326322_T1", "type": "Gene", "text": [ "RPGR" ], "offsets": [ [ 16, 20 ] ], "normalized": [] }, { "id": "9326322_T2", "type": "Gene", "text": [ "RP3" ], "offsets": [ [ 272, 275 ] ], "normalized": [] }, { "id": "9326322_T3", "type": "Gene", "text": [ "RPGR" ], "offsets": [ [ 556, 560 ] ], "normalized": [] }, { "id": "9326322_T4", "type": "Gene", "text": [ "RP3" ], "offsets": [ [ 502, 505 ] ], "normalized": [] }, { "id": "9326322_T5", "type": "Gene", "text": [ "RPGR" ], "offsets": [ [ 715, 719 ] ], "normalized": [] }, { "id": "9326322_T6", "type": "Gene", "text": [ "(RP3)" ], "offsets": [ [ 778, 783 ] ], "normalized": [] }, { "id": "9326322_T7", "type": "Gene", "text": [ "RPGR" ], "offsets": [ [ 954, 958 ] ], "normalized": [] }, { "id": "9326322_T8", "type": "Gene", "text": [ "RP3" ], "offsets": [ [ 900, 903 ] ], "normalized": [] }, { "id": "9326322_T9", "type": "Gene", "text": [ "RPGR" ], "offsets": [ [ 1226, 1230 ] ], "normalized": [] }, { "id": "9326322_T10", "type": "Gene", "text": [ "RPGR" ], "offsets": [ [ 1310, 1314 ] ], "normalized": [] }, { "id": "9326322_T11", "type": "Gene", "text": [ "RP3" ], "offsets": [ [ 1351, 1354 ] ], "normalized": [] }, { "id": "9326322_T12", "type": "Gene", "text": [ "RPGR" ], "offsets": [ [ 1455, 1459 ] ], "normalized": [] }, { "id": "9326322_T13", "type": "Gene", "text": [ "(retinitis pigmentosa GTPase regulator)" ], "offsets": [ [ 561, 600 ] ], "normalized": [] } ]

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[ { "id": "9326322_R1", "type": "Equals", "arg1_id": "9326322_T13", "arg2_id": "9326322_T3", "normalized": [] } ]

[ { "id": "9199548__text", "type": "abstract", "text": [ "Genetics of narcolepsy and other sleep disorders.\n" ], "offsets": [ [ 0, 50 ] ] } ]

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[ { "id": "9012405__text", "type": "abstract", "text": [ "A mutation in the XPB/ERCC3 DNA repair transcription gene, associated with trichothiodystrophy. Trichothiodystrophy (TTD) is a rare, autosomal recessive disorder characterized by sulfur-deficient brittle hair and nails, mental retardation, impaired sexual development, and ichthyosis. Photosensitivity has been reported in approximately 50% of the cases, but no skin cancer is associated with TTD. Virtually all photosensitive TTD patients have a deficiency in the nucleotide excision repair (NER) of UV-induced DNA damage that is indistinguishable from that of xeroderma pigmentosum (XP) complementation group D (XP-D) patients. DNA repair defects in XP-D are associated with two additional, quite different diseases; XP, a sun-sensitive and cancer-prone repair disorder, and Cockayne syndrome (CS), a photosensitive condition characterized by physical and mental retardation and wizened facial appearance. One photosensitive TTD case constitutes a new repair-deficient complementation group, TTD-A. Remarkably, both TTD-A and XP-D defects are associated with subunits of TFIIH, a basal transcription factor with a second function in DNA repair. Thus, mutations in TFIIH components may, on top of a repair defect, also cause transcriptional insufficiency, which may explain part of the non-XP clinical features of TTD. Besides XPD and TTDA, the XPB gene product is also part of TFIIH. To date, three patients with the remarkable conjunction of XP and CS but not TTD have been assigned to XP complementation group B (XP-B). Here we present the characterization of the NER defect in two mild TTD patients (TTD6VI and TTD4VI) and confirm the assignment to X-PB. The causative mutation was found to be a single base substitution resulting in a missense mutation (T119P) in a region of the XPB protein completely conserved in yeast, Drosophila, mouse, and man. These findings define a third TTD complementation group, extend the clinical heterogeneity associated with XP-B, stress the exclusive relationship between TTD and mutations in subunits of repair/transcription factor TFIIH, and strongly support the concept of \"transcription syndromes.\"\n" ], "offsets": [ [ 0, 2143 ] ] } ]

[ { "id": "9012405_T1", "type": "Gene", "text": [ "XPB/ERCC3" ], "offsets": [ [ 18, 27 ] ], "normalized": [] }, { "id": "9012405_T2", "type": "Gene", "text": [ "XPB" ], "offsets": [ [ 1346, 1349 ] ], "normalized": [] }, { "id": "9012405_T3", "type": "SNP", "text": [ "T119P" ], "offsets": [ [ 1760, 1765 ] ], "normalized": [] }, { "id": "9012405_T4", "type": "Gene", "text": [ "XPB" ], "offsets": [ [ 1786, 1789 ] ], "normalized": [] }, { "id": "9012405_T5", "type": "Gene", "text": [ "TFIIH" ], "offsets": [ [ 2073, 2078 ] ], "normalized": [] } ]

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[ { "id": "9012405_R1", "type": "AssociatedTo", "arg1_id": "9012405_T3", "arg2_id": "9012405_T4", "normalized": [] } ]

[ { "id": "9382097__text", "type": "abstract", "text": [ "Neonatal, lethal noncompaction of the left ventricular myocardium is allelic with Barth syndrome. Loss-of-function mutations in the G4.5 gene have been shown to cause Barth syndrome (BTHS), an X-linked disorder characterized by cardiac and skeletal myopathy, short stature, and neutropenia. We recently reported a family with a severe X-linked cardiomyopathy described as isolated noncompaction of the left ventricular myocardium (INVM). Other findings associated with BTHS (skeletal myopathy, neutropenia, growth retardation, elevated urinary organic acids, and mitochondrial abnormalities) were either absent or inconsistent. A linkage study of the X chromosome localized INVM to the Xq28 region near the BTHS locus, suggesting that these disorders are allelic. We screened the G4.5 gene for mutations in this family with SSCP and direct sequencing and found a novel glycine-to-arginine substitution at position 197. This position is conserved in a homologous Caenorhabditis elegans protein. We conclude that INVM is a severe allelic variant of BTHS with a specific effect on the heart. This finding provides further structure-function information about the G4.5 gene product and has implications for unexplained cases of severe infantile hypertrophic cardiomyopathy in males.\n" ], "offsets": [ [ 0, 1279 ] ] } ]

[ { "id": "9382097_T1", "type": "Gene", "text": [ "G4.5" ], "offsets": [ [ 780, 784 ] ], "normalized": [] }, { "id": "9382097_T2", "type": "Gene", "text": [ "G4.5" ], "offsets": [ [ 1160, 1164 ] ], "normalized": [] }, { "id": "9382097_T3", "type": "SNP", "text": [ "glycine-to-arginine substitution at position 197" ], "offsets": [ [ 869, 917 ] ], "normalized": [] } ]

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[ { "id": "9382104__text", "type": "abstract", "text": [ "A novel locus for autosomal dominant nonsyndromic hearing loss, DFNA13, maps to chromosome 6p. Nonsyndromic hearing loss (NSHL) is the most common type of hearing impairment in the elderly. Environmental and hereditary factors play an etiologic role, although the relative contribution of each is unknown. To date, 39 NSHL genes have been localized. Twelve produce autosomal dominant hearing loss, most frequently postlingual in onset and progressive in nature. We have ascertained a large, multigenerational family in which a gene for autosomal dominant NSHL is segregating. Affected individuals experience progressive hearing loss beginning in the 2d-4th decades, eventually making the use of amplification mandatory. A novel locus, DFNA13, was identified on chromosome 6p; the disease gene maps to a 4-cM interval flanked by D6S1663 and D6S1691, with a maximum two-point LOD score of 6.409 at D6S299.\n" ], "offsets": [ [ 0, 904 ] ] } ]

[ { "id": "9382104_T1", "type": "Gene", "text": [ "DFNA13," ], "offsets": [ [ 64, 71 ] ], "normalized": [] }, { "id": "9382104_T2", "type": "Gene", "text": [ "DFNA13," ], "offsets": [ [ 735, 742 ] ], "normalized": [] } ]

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