pmid stringlengths 5 8 | title stringlengths 17 342 | abstract stringlengths 1 4.53k | all_entity_list listlengths 2 73 | label listlengths 1 80 | intra-sentence listlengths 1 80 | head_gene_entity listlengths 1 80 | tail_diease_entity listlengths 1 80 | head_name listlengths 1 80 | tail_name listlengths 1 80 |
|---|---|---|---|---|---|---|---|---|---|
8640238 | A novel splice-site mutation in the gamma subunit of the epithelial sodium channel gene in three pseudohypoaldosteronism type 1 families. | Pseudohypoaldosteronism type 1 (PHA1, OMIM 264350) is an uncommon inherited disorder characterized by salt-wasting and end-organ unresponsiveness to mineralocorticoids. A complete genome search using homozygosity mapping in eleven consanguineous families with PHA1 provided conclusive evidence of linkage with heterogeneity. The disease locus mapped to chromosome 16p12.2-13.11 in six families and to 12p13.1-pter in the other five families. These two chromosomal regions harbour the genes encoding the three subunits of the human amiloride sensitive epithelial sodium channel (hENaC): SCNN1B and SCNN1G on 16p and SCNN1A on 12p. Our linkage results have been further supported by the recent report of mutations in the alpha and beta subunit genes in PHA1 patients. We now report the identification of a 3' splice site mutation in SCNN1G (318-1 G-->A) in three families showing linkage to 16p. Abnormal splicing results with the production of two messenger RNAs, one arising from activation of an adjacent cryptic splice site and the other from skipping of the downstream exon. The two corresponding mutant gamma hENaC subunits are predicted to have three highly conserved amino acids in the extracellular domain replaced by a novel amino acid (KYS106-108-->N) and truncation from 649 to 134 amino acids respectively. These three families all originate from the Indian sub-continent and the probands have severe generalized PHA. They share a common haplotype which suggests the presence of a founder mutation in this sub-population. | [
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"text_name": "pseudohypoaldosteronism type 1"
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"entity_id": "6340",
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"text_name": "SCNN1G"
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] | [
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"text_name": "pseudohypoaldosteronism type 1"
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"entity_id": "D010381",
"entity_type": "Disease",
"text_name": "PHA"
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] | [
"SCNN1G",
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"PHA"
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8644702 | Founding BRCA1 mutations in hereditary breast and ovarian cancer in southern Sweden. | Nine different germ-line mutations in the BRCA1 breast and ovarian cancer susceptibility gene were identified in 15 of 47 kindreds from southern Sweden, by use of SSCP and heteroduplex analysis of all exons and flanking intron region and by a protein-truncation test for exon 11, followed by direct sequencing. All but one of the mutations are predicted to give rise to premature translation termination and include seven frameshift insertions or deletions, a nonsense mutation, and a splice acceptor site mutation. The remaining mutation is a missense mutation (Cys61Gly) in the zinc-binding motif. Four novel Swedish founding mutations were identified: the nucleotide 2595 deletion A was found in five families, the C 1806 T nonsense mutation in three families, the 3166 insertion TGAGA in three families, and the nucleotide 1201 deletion 11 in two families. Analysis of the intragenic polymorphism D17S855 supports common origins of the mutations. Eleven of the 15 kindreds manifesting BRCA1 mutations were breast-ovarian cancer families, several of them with a predominant ovarian cancer phenotype. The set of 32 families in which no BRCA1 alterations were detected included 1 breast-ovarian cancer kindred manifesting clear linkage to the BRCA1 region and loss of the wild-type chromosome in associated tumors. Other tumor types found in BRCA1 mutation/haplotype carriers included prostatic, pancreas, skin, and lung cancer, a malignant melanoma, an oligodendroglioma, and a carcinosarcoma. In all, 12 of 16 kindreds manifesting BRCA1 mutation or linkage contained ovarian cancer, as compared with only 6 of the remaining 31 families (P<.001). The present study confirms the involvement of BRCA1 in disease predisposition for a subset of hereditary breast cancer families often characterized by ovarian cancers. | [
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"text_name": "hereditary breast cancer"
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"entity_type": "Disease",
"text_name": "carcinosarcoma"
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"text_name": "hereditary breast and ovarian cancer"
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"text_name": "prostatic, pancreas, sk... | [
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8644733 | Uroporphyrinogen decarboxylase: complete human gene sequence and molecular study of three families with hepatoerythropoietic porphyria. | A deficiency in uroporphyrinogen decarboxylase (UROD) enzyme activity, the fifth enzyme of the heme biosynthetic pathway, is found in patients with sporadic porphyria cutanea tarda (s-PCT), familial porphyria cutanea tarda (f-PCT), and hepatoerythropoietic porphyria (HEP). Subnormal UROD activity is due to mutations of the UROD gene in both f-PCT and HEP, but no mutations have been found in s-PCT. Genetic analysis has determined that f-PCT is transmitted as an autosomal dominant trait. In contrast, HEP, a severe form of cutaneous porphyria, is transmitted as an autosomal recessive trait. HEP is characterized by a profound deficiency of UROD activity, and the disease is usually manifest in childhood. In this study, a strategy was designed to identify alleles responsible for the HEP phenotype in three unrelated families. Mutations of UROD were identified by direct sequencing of four amplified fragments that contained the entire coding sequence of the UROD gene. Two new missense mutations were observed at the homoallelic state: P62L (proline-to-leucine substitution at codon 62) in a Portuguese family and Y311C (tyrosine-to-cysteine substitution at codon 311) in an Italian family. A third mutation, G281E, was observed in a Spanish family. This mutation has been previously described in three families from Spain and one from Tunisia. In the Spanish family described in this report, a paternal uncle of the proband developed clinically overt PCT as an adult and proved to be heterozygous for the G281E mutation. Mutant cDNAs corresponding to the P62L and Y311C changes detected in these families were created by site-directed mutagenesis. Recombinant proteins proved to have subnormal enzyme activity, and the Y311C mutant was thermolabile. | [
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"text_name": "deficiency in uroporphyrinogen decarboxylase"
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"entity_id": "D017121",
"entity_type": "Disease",
"text_name": "HEP"
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"Uroporphyrinogen decarboxylase",
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"HEP"
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8655141 | Systematic screening for mutations in the human serotonin-2A (5-HT2A) receptor gene: identification of two naturally occurring receptor variants and association analysis in schizophrenia. | A statistically significant association between a silent mutation (102T/C) in the serotonin-2A (5-HT2A) receptor gene and schizophrenia has recently been reported in a sample of Japanese patients and healthy controls. This finding suggests that genetic predisposition to schizophrenia may be affected by a functional 5-HT2A receptor variant that is in linkage disequilibrium with 102T/C. In the present study, we have sought to identify genetic variation in the 5-HT2A receptor gene by screening genomic DNA samples from 91 unrelated subjects comprising 45 patients with schizophrenia and 46 healthy controls by using single-strand conformation analysis. We have identified four nucleotide sequence variants. Two sequence changes would result in protein alterations: a substitution of threonine by asparagine at position 25 (Thr25Asn), and a substitution of histidine by tyrosine at position 452 (His452Tyr). In order to test for a possible contribution to the development of schizophrenia, we have determined allele frequencies in extended samples of unrelated patients and healthy controls. The two amino acid substitutions are found with similar frequencies in patients and controls, indicating that the presence of these variants is not causally related to the development of schizophrenia. However, the reported association of the non-coding polymorphism 102T/C with the disease has also been detected in our sample (P=0.041, odds ratio=1.28, 95% confidence interval 1.012-1.623). | [
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"entity_type": "Disease",
"text_name": "schizophrenia"
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"entity_id": "D012559",
"entity_type": "Disease",
"text_name": "schizophrenia"
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"text_name": "5-HT2A receptor"
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] | [
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"entity_id": "D012559",
"entity_type": "Disease",
"text_name": "schizophrenia"
}
] | [
"5-HT2A receptor"
] | [
"schizophrenia"
] |
8666322 | Admission levels of serum Gc-globulin: predictive value in fulminant hepatic failure. | Gc-globulin scavenges actin released from necrotic hepatocytes to the extracellular space. In 77 patients with fulminant hepatic failure (FHF) (excluding patients treated with liver transplantation), admission levels of serum Gc-globulin and degree of complexing with monomeric actin (complex ratio) were determined to evaluate their predictive values in relation to survival/nonsurvival. Gc-globulin levels were significantly reduced in 47 nonsurvivors, compared with 30 survivors (96 +/- 71 mg/L vs. 169 +/- 101 mg/L, P < .001), whereas the complex ratio in nonsurvivors did not differ significantly from that of survivors. Gc-globulin levels were significantly lower in 59 patients with non-acetaminophen-induced FHF, compared with 18 patients with acetaminophen-induced FHF (P < .01). Using a cutoff level of serum Gc-globulin of 100 mg/L, a lesser value correctly predicted nonsurvival in 79 percent of patients with non-acetaminophen-induced FHF, whereas a higher value predicted survival in 60 percent. In patients with acetaminophen-induced FHF, nonsurvival was correctly predicted in 100 percent of patients and survival in 53 percent. In comparison, the King's College Hospital (KCH) criteria correctly predicted nonsurvival and survival in 69 percent and 57 percent, respectively, of the same non-acetaminophen-induced FHF patients and in 60 percent and 38 percent, respectively, of the acetaminophen-induced FHF patients. Thus, in our study population, the predictive properties of Gc-globulin were in the same range as the KCH criteria. An advantage of Gc-globulin is that it gives an estimate of the outcome already on admission. Acute liver transplantation should be considered in FHF patients with Gc-globulin less than 100 mg/L. | [
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"entity_type": "Disease",
"text_name": "fulminant hepatic failure"
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"entity_id": "D017114",
"entity_type": "Disease",
"text_name": "fulminant hepatic failure"
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"text_name": "Gc-globulin"
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] | [
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"entity_id": "D017114",
"entity_type": "Disease",
"text_name": "fulminant hepatic failure"
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] | [
"Gc-globulin"
] | [
"fulminant hepatic failure"
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8695804 | Identification of Bruton's tyrosine kinase (Btk) gene mutations and characterization of the derived proteins in 35 X-linked agammaglobulinemia families: a nationwide study of Btk deficiency in Japan. | Deficiencies of Bruton's tyrosine kinase (Btk) have been implicated in the pathogenesis of human X-linked agammaglobulinemia (XLA). The distinctive phenotype observed in B-cell deficiency indicates the crucial role of Btk in B-cell development. This report describes a nationwide study of Btk deficiency in Japan, covering 51 XLA patients (35 independent families). Along with the identification of mutations, the resulting protein products were characterized by an in vitro kinase assay and a Western blot analysis. Thirty-one of the families were found to have mutations in the coding region of Btk. Although mutations were not found in the cDNA of 4 families, the Btk transcripts of these patients were greatly reduced. The identification of several novel missense mutations, in combination with the result of other studies, clarified the presence of two (missense) mutation hot spots, one in the SH1 and the other in the PH domain. The absence of kinase activity seen in 32 of the families underscored the importance of Btk protein analysis as a diagnostic indicator of XLA. The protein analysis also clarified the different effects of missense mutations on kinase activity and protein stability. | [
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"end_idx": "142",
"entity_id": "C537409",
"entity_type": "Disease",
"text_name": "X-linked agammaglobulinemia"
},
{
"begin_idx": "175",
"end_idx": "189",
"entity_id": "C537409",
"entity_type": "Disease",
"text_name": "Btk deficiency"
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] | [
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"text_name": "Bruton's tyrosine kinase"
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{
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"entity_id": "695",
"entity_type": "Gene",
"text_name": "Bruton's tyrosine kinase"
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] | [
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"text_name": "Deficiencies of Bruton's tyrosine kinase"
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"entity_id": "D016393",
"entity_type": "Disease",
"text_name": "B-cell deficiency"
... | [
"Bruton's tyrosine kinase",
"Bruton's tyrosine kinase"
] | [
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"B-cell deficiency"
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8703060 | Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. | Pycnodysostosis, an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature, maps to chromosome 1q21. Cathepsin K, a cysteine protease gene that is highly expressed in osteoclasts, localized to the pycnodysostosis region. Nonsense, missense, and stop codon mutations in the gene encoding cathepsin K were identified in patients. Transient expression of complementary DNA containing the stop codon mutation resulted in messenger RNA but no immunologically detectable protein. Thus, pycnodysostosis results from gene defects in a lysosomal protease with highest expression in osteoclasts. These findings suggest that cathepsin K is a major protease in bone resorption, providing a possible rationale for the treatment of disorders such as osteoporosis and certain forms of arthritis. | [
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"entity_id": "D001168",
"entity_type": "Disease",
"text_name": "arthritis"
},
{
"begin_idx": "169",
"end_idx": "182",
"entity_id": "D006130",
"entity_type": "Disease",
"text_name": "short stature"
},
{
"begin_idx": "844",
... | [
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] | [
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] | [
{
"begin_idx": "47",
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"entity_id": "1513",
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"text_name": "cathepsin K"
},
{
"begin_idx": "224",
"end_idx": "241",
"entity_id": "1508",
"entity_type": "Gene",
"text_name": "cysteine protease"
}
] | [
{
"begin_idx": "0",
"end_idx": "15",
"entity_id": "D058631",
"entity_type": "Disease",
"text_name": "Pycnodysostosis"
},
{
"begin_idx": "150",
"end_idx": "164",
"entity_id": "D010026",
"entity_type": "Disease",
"text_name": "osteosclerosis"
}
] | [
"cathepsin K",
"cysteine protease"
] | [
"Pycnodysostosis",
"osteosclerosis"
] |
8721777 | Association of the glycogen synthase locus on 19q13 with NIDDM in Pima Indians. | Skeletal muscle glycogen synthase (encoded by GYS1 on chromosome 19q13.3) is the rate-limiting enzyme in insulin-mediated non-oxidative glucose disposal. Our previous studies have demonstrated an impairment of insulin-stimulated GYS1 activities in insulin-resistant Pima Indians, and associations of non-insulin-dependent diabetes mellitus (NIDDM) with the GYS1 locus were reported recently in Finnish and Japanese populations. We have performed linkage and association analyses of GYS1 and seven additional DNA markers on 19q with NIDDM, and with parameters of insulin action in the Pima Indians. We have found a significant association of NIDDM with GYS1 genotypes (p = 0.009), and with common GYS1 alleles (p = 0.022) in the Pima Indians. We have performed a detailed comparative analysis of the GYS1 gene, mRNA, and protein product in insulin-sensitive and insulin-resistant Pima Indians. No mutations in GYS1 coding sequences were detected; nor did we find alterations of GYS1 mRNA expression or of its basal enzymatic activity in insulin-resistant Pima Indians. These results contrasted with a 25% reduction of immunoreactive protein in insulin-resistant subjects as detected by Western blotting with an antibody specific for the C-terminal end of GYS1 (t-test p = 0.024; Wilcoxon's rank-sum test, p = 0.04). Because no mutations were detected in the DNA encoding this epitope, the difference in immunoreactivity may reflect post-translational modification(s) of the protein rather than a difference in the gene itself, or it could have occurred by chance. We conclude that our data do not indicate alterations in the GYS1 gene as the cause for the observed association, and that a different locus near GYS1 may be the contributing genetic element. | [
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"entity_type": "Disease",
"text_name": "NIDDM"
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"entity_id": "D003924",
"entity_type": "Disease",
"text_name": "non-insulin-dependent diabetes mellitus"
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"text_name": "Skeletal muscle glycogen synthase"
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{
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"entity_id": "3630",
"entity_type": "Gene",
"text_name": "insulin"
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"text_name": "non-insulin-dependent diabetes mellitus"
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"text_name": "NIDDM"
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"Skeletal muscle glycogen synthase",
"insulin"
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"non-insulin-dependent diabetes mellitus",
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8721778 | Variant sequences of the Hexokinase II gene in familial NIDDM. | Hexokinase II (HKII) plays a central role in the intracellular metabolism of glucose in skeletal muscle, catalysing the phosphorylation of glucose to glucose 6-phosphate. It is therefore considered to be a potentially important candidate gene in the development of insulin resistance and non-insulin-dependent diabetes mellitus (NIDDM). The aim of this study was to screen the HKII gene for mutations in NIDDM subjects from insulin-resistant families. Insulin sensitivity was assessed in unaffected first degree relatives from families with two or more living NIDDM subjects, and 15 families were identified as being insulin resistant. In 15 NIDDM subjects (one from each family) and 4 normoglycaemic control subjects, all 18 exons of the HKII gene were amplified by the polymerase chain reaction, and the products screened for mutations using a combination of single-stranded conformational polymorphism analysis and direct sequencing. Six sequence variations were detected in the NIDDM subjects; four silent polymorphisms [GAT vs GAC at codon 251 in exon 7, AAT vs AAC at codon 692 in exon 15, CCG vs CCC at codon 736 in exon 15, and CTG vs CTA at codon 766 in exon 16]; a single base change [T-->C], 22 base pairs distal to the exon-intron junction of exon 17 in the 5'-splice donor; and a single amino acid substitution [Gln142-->His] in exon 4, which was identified in 6 of the 15 NIDDM subjects. The frequency of the mutated codon 142 allele however, was comparable between NIDDM subjects with familial NIDDM (n = 56) and normoglycaemic control subjects (n = 48) (18.8% and 14.6% for NIDDM subjects and control subjects respectively; chi 2 = 0.6, p > 0.25). In addition, measures of insulin sensitivity were comparable in normal glucose tolerant subjects with (n = 20) and without (n = 40) the codon 142 polymorphism. IN CONCLUSION: (1) mutations in the coding regions of the HKII gene are unlikely to be major determinants in the development of insulin resistance and familial NIDDM; although (2) the influence of the codon 142 mutation in combination with other abnormalities of the insulin-signalling pathway on insulin action remain to be addressed. | [
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"text_name": "NIDDM"
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"entity_id": "D003924",
"entity_type": "Disease",
"text_name": "non-insulin-dependent diabetes mellitus"
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"text_name": "non-insulin-dependent diabetes mellitus"
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] | [
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] | [
"non-insulin-dependent diabetes mellitus"
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8723683 | Mutations in the BRCA1 gene in Japanese breast cancer patients. | Predisposing germline mutations in the BRCA1 gene were identified recently in families with 17 q-linked breast and ovarian cancers. Using single-strand conformation polymorphism (SSCP) analysis, we examined primary breast cancers for mutations in coding exons of BRCA1 in a panel of 103 patients, of whom all either represented early-onset cases (< 35 of age), were members of multiply-affected families, and/or had developed bilateral breast cancers. Mutations were detected in tumors from four patients, all of whom had developed breast cancers bilaterally: a frame-shift due to a 2-bp deletion at codon 797; a nonsense mutation at codon 1214; and two missense mutations, one at codon 271 leading to Val-->Met substitution, and the other at codon 1150 leading to Pro-->Ser substitution. In each case the same mutation was present in constitutional DNA. The mean age of onset was 49 years among the Japanese carriers of BRCA1 mutations identified in this study, in contrast to the mean age of 35 observed among carriers of BRCA1 mutations in a similar U.S. study (Futreal et al., 1994). The evidence reported here supports a rather limited role of BRCA1 in breast carcinogenesis. | [
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"entity_type": "Disease",
"text_name": "breast cancer"
},
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"end_idx": "293",
"entity_id": "D001943",
"entity_type": "Disease",
"text_name": "breast cancers"
},
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"begin_idx": "500",... | [
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] | [
{
"begin_idx": "17",
"end_idx": "22",
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"entity_type": "Gene",
"text_name": "BRCA1"
},
{
"begin_idx": "327",
"end_idx": "332",
"entity_id": "672",
"entity_type": "Gene",
"text_name": "BRCA1"
}
] | [
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"text_name": "breast cancers"
},
{
"begin_idx": "543",
"end_idx": "549",
"entity_id": "D009369",
"entity_type": "Disease",
"text_name": "tumors"
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] | [
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"breast cancers",
"tumors"
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8725748 | Allelic association but only weak evidence for linkage to the apolipoprotein E locus in late-onset Swedish Alzheimer families. | An association between the epsilon 4 allele of the apolipoprotein E gene (APOE) and late-onset Alzheimer's disease (AD) was recently demonstrated. In order to confirm the association and to gauge the ability of standard genetic linkage methods to identify susceptibility genes, we investigated 15 Swedish late-onset Ad families. We found an association of familial AD to the APOE epsilon 4 allele (P = 0.01) but no indication of linkage to the APOE region using 2-point linkage analysis, and only weak evidence using the affected pedigree-member (APM) method. Our results confirm an APOE epsilon 4 association with late-onset familial AD and indicate that susceptibility genes can easily be missed when using standard lod score and APM genetic linkage analysis. | [
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"entity_id": "D000544",
"entity_type": "Disease",
"text_name": "Alzheimer"
},
{
"begin_idx": "222",
"end_idx": "241",
"entity_id": "D000544",
"entity_type": "Disease",
"text_name": "Alzheimer's disease"
},
{
"begin_idx": "24... | [
"Yes"
] | [
true
] | [
{
"begin_idx": "62",
"end_idx": "78",
"entity_id": "348",
"entity_type": "Gene",
"text_name": "apolipoprotein E"
}
] | [
{
"begin_idx": "222",
"end_idx": "241",
"entity_id": "D000544",
"entity_type": "Disease",
"text_name": "Alzheimer's disease"
}
] | [
"apolipoprotein E"
] | [
"Alzheimer's disease"
] |
8728326 | Homozygosity for two point mutations in the lipoprotein lipase (LPL) gene in a patient with familial LPL deficiency: LPL(Asp9-->Asn, Tyr262-->His). | Familial lipoprotein lipase (LPL) deficiency is an inherited disorder of lipoprotein metabolism characterized by hypertriglyceridemia and recurrent episodes of abdominal pain and pancreatitis. We have studied the genetic basis of LPL deficiency in a 62-year-old black male with undetectable pre- and post-heparin plasma LPL mass and activity, DNA sequence analysis of the patient's LPL cDNA and gene as well as digestion with Bcl I and Asu I revealed that the proband is a homozygote for two separate gene defects. One mutation changed a G to an A, resulting in the conversion of amino acid 9 of the mature protein, aspartic acid (GAC), to asparagine (AAC). The second substitution, a C for a T, replaced tyrosine (TAC) at residue 262 with histidine (CAC). Northern blot analysis of monocyte-derived macrophage RNA demonstrated the presence of LPL mRNA of approximately normal size and quantity when compared to control. Expression of both mutations separately (pCMV-9 and pCMV-262) or in combination (pCMV-9+262) in human embryonal kidney-293 cells demonstrated that LPL-9 had approximately 80% the specific activity of wild type LPL, but LPL-262 and LPL-9+262 had no enzymic activity, thus establishing the functional significance of the LPL-262 defect. Despite an absolute deficiency of LPL mass and activity demonstrated by analysis of patient post-heparin plasma, in vitro expression of both LPL mutants was normal, suggesting that the absence of LPL in patient post-heparin plasma was a result of altered in vivo processing. Analysis of the heparin binding properties of the mutant enzymes by heparin-Sepharose affinity chromatography indicated that most of the LPL-262 mass was present in an inactive peak, which like the normal LPL monomer, eluted at 0.8 M NaCl. Thus, the Tyr262 --> His mutation may alter the stability of the LPL dimer, leading to the formation of inactive LPL-262 monomer which exhibits reduced heparin affinity. Based on these results, we propose that, in vivo, enhanced formation of LPL-9+262 monomer leads to abnormal binding of the mutant lipase to endothelial glycosaminoglycans ultimately resulting in enhanced catabolism of the mutant enzyme and lower enzyme mass in post-heparin plasma. | [
{
"begin_idx": "92",
"end_idx": "115",
"entity_id": "D008072",
"entity_type": "Disease",
"text_name": "familial LPL deficiency"
},
{
"begin_idx": "148",
"end_idx": "192",
"entity_id": "D008072",
"entity_type": "Disease",
"text_name": "Familial lipoprotein lipase (LPL) def... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "44",
"end_idx": "62",
"entity_id": "4023",
"entity_type": "Gene",
"text_name": "lipoprotein lipase"
},
{
"begin_idx": "1816",
"end_idx": "1819",
"entity_id": "4023",
"entity_type": "Gene",
"text_name": "LPL"
}
] | [
{
"begin_idx": "148",
"end_idx": "192",
"entity_id": "D008072",
"entity_type": "Disease",
"text_name": "Familial lipoprotein lipase (LPL) deficiency"
},
{
"begin_idx": "261",
"end_idx": "281",
"entity_id": "D015228",
"entity_type": "Disease",
"text_name": "hypertriglyceri... | [
"lipoprotein lipase",
"LPL"
] | [
"Familial lipoprotein lipase (LPL) deficiency",
"hypertriglyceridemia"
] |
8730300 | C-reactive protein and haptoglobin in the evaluation of a community-based malaria control programme. | When cross-sectional surveys are used to evaluate malaria intervention programmes in the community, the prevalence of morbidity is difficult to assess because of the fluctuating nature of malarial fever. We have therefore investigated the impact of bed net usage on 2 surrogate markers of malarial morbidity: (i) elevated C-reactive protein (CRP) (> 8 mg/L) plus detectable parasitaemia, as an indicator of malaria-induced acute-phase response; and (ii) reduced haptoglobin levels (< 180 mg/L), which in this population indicates malaria-induced intravascular haemolysis. Among 1505 Gambian children 1-5 years old, examined on a single occasion at the end of the malarial transmission season, 5% had parasitaemia plus fever, while 24% had parasitaemia plus elevated CRP, and 35% had low haptoglobin. The proportion of children who had parasitaemia plus elevated CRP was significantly lower among those who had slept under insecticide-treated bed nets than among those who did not use a bed net (16% vs. 34%, P < 0.003), and the proportion with low haptoglobin differed similarly (24% vs. 49%, P < 0.003). Use of an untreated bed net had a weaker effect on both indices (22% had parasitaemia plus elevated CRP, 34% had low haptoglobin). CRP and haptoglobin are simple and inexpensive to measure in large numbers of people, and these results suggest that they could be useful for the assessment of malaria intervention programmes. | [
{
"begin_idx": "647",
"end_idx": "671",
"entity_id": "D004211",
"entity_type": "Disease",
"text_name": "intravascular haemolysis"
},
{
"begin_idx": "289",
"end_idx": "303",
"entity_id": "D005334",
"entity_type": "Disease",
"text_name": "malarial fever"
},
{
"begin... | [
"Yes",
"Yes",
"No",
"No"
] | [
true,
true,
false,
false
] | [
{
"begin_idx": "0",
"end_idx": "18",
"entity_id": "1401",
"entity_type": "Gene",
"text_name": "C-reactive protein"
},
{
"begin_idx": "23",
"end_idx": "34",
"entity_id": "3240",
"entity_type": "Gene",
"text_name": "haptoglobin"
},
{
"begin_idx": "867",
"end_idx... | [
{
"begin_idx": "74",
"end_idx": "81",
"entity_id": "D008288",
"entity_type": "Disease",
"text_name": "malaria"
},
{
"begin_idx": "74",
"end_idx": "81",
"entity_id": "D008288",
"entity_type": "Disease",
"text_name": "malaria"
},
{
"begin_idx": "289",
"end_idx":... | [
"C-reactive protein",
"haptoglobin",
"CRP",
"haptoglobin"
] | [
"malaria",
"malaria",
"malarial fever",
"malarial fever"
] |
8740916 | Association analyses of NsiI RFLP of human insulin receptor gene in hypertensives. | Plasma angiotensinogen is elevated in essential hypertensives and shows a strong correlation with blood pressure. Patients with hypertension often display insulin resistance and we have found previously an association of a RsaI RFLP in intron 9 of the insulin receptor gene (INSR) with hypertension. Since insulin resistance is accompanied by hyperinsulinaemia and insulin can stimulate angiotensinogen production, we hypothesized that hypertension-associated genotypes of INSR may be associated with elevation in plasma angiotensinogen. We used PCR to detect a NsiI RFLP in exon 8 of INSR and examined its relationship with plasma angiotensinogen, as well as hypertension, in 134 Caucasian hypertensives with two hypertensive parents and in 126 normotensives. Plasma angiotensinogen tracked weakly with the major allele of the NsiI RFLP in hypertensives (p = 0.08). Moreover, the frequency of this allele was higher in lean hypertensives than in lean normotensives (p < 0.05) and in normolipidaemic hypertensives than normolipidaemic normotensives (p < 0.02). The present study thus suggests that there could be a relationship of plasma angiotensinogen with INSR genotype, and of each with hypertension. | [
{
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"end_idx": "81",
"entity_id": "D006973",
"entity_type": "Disease",
"text_name": "hypertensives"
},
{
"begin_idx": "131",
"end_idx": "144",
"entity_id": "D006973",
"entity_type": "Disease",
"text_name": "hypertensives"
},
{
"begin_idx": "211",
... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "43",
"end_idx": "59",
"entity_id": "3643",
"entity_type": "Gene",
"text_name": "insulin receptor"
},
{
"begin_idx": "715",
"end_idx": "730",
"entity_id": "183",
"entity_type": "Gene",
"text_name": "angiotensinogen"
}
] | [
{
"begin_idx": "68",
"end_idx": "81",
"entity_id": "D006973",
"entity_type": "Disease",
"text_name": "hypertensives"
},
{
"begin_idx": "211",
"end_idx": "223",
"entity_id": "D006973",
"entity_type": "Disease",
"text_name": "hypertension"
}
] | [
"insulin receptor",
"angiotensinogen"
] | [
"hypertensives",
"hypertension"
] |
8741040 | Pentoxifylline reduces plasma tumour necrosis factor-alpha concentration in premature infants with sepsis. | Increased plasma tumour necrosis factor alpha (TNF) concentration correlates with mortality in sepsis. We suggested that pentoxifylline (PTXF), which is known to inhibit TNF production, may improve survival and attenuate clinical symptoms of sepsis in neonates. Plasma TNF levels were evaluated in 29 newborn infants with sepsis. Patients were randomly assigned into two groups, receiving PTXF in a dose of 5 mg/kg per hour for 6 h or placebo (saline), on 3 successive days. Both groups were subjected to the same conventional therapy. TNF was evaluated before and after PTXF or placebo administration on the 1st and 3rd days of therapy. There was a statistically significant decrease in plasma TNF level in the PTXF group when the values before the first and after the last PTXF infusion were compared [mean: 671.5 pg/ml; SD: 438; med: 729.6 vs mean: 41.0 pg/ml; SD: 64.1; med: 11.5; P < 0.000004]. In the placebo group, decrease was not significant [mean: 633.0 pg/ml SD: 488.6; med: 618.9 vs 246.9 pg/ml; SD: 243.9; med: 191.0]. A significantly higher plasma TNF level, evaluated after the last PTXF infusion, was found in the placebo group [246.9 pg/ml vs 41.0 pg/ml; P < 0.001]. Only one of four infants with signs of shock in the placebo group survived, whereas all of five newborns with symptoms of shock in the PTXF group survived [P < 0.04]. An increased incidence of metabolic acidosis [P < 0.05], necrotizing enterocolitis [P < 0.04] and renal insufficiency [P < 0.05] was observed in infants in the placebo group. CONCLUSION: PTXF inhibits production of TNF and may have therapeutic value in the treatment of premature infants with sepsis complicated by shock. | [
{
"begin_idx": "1484",
"end_idx": "1502",
"entity_id": "D000138",
"entity_type": "Disease",
"text_name": "metabolic acidosis"
},
{
"begin_idx": "30",
"end_idx": "45",
"entity_id": "D009369",
"entity_type": "Disease",
"text_name": "tumour necrosis"
},
{
"begin_idx"... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "154",
"end_idx": "157",
"entity_id": "7124",
"entity_type": "Gene",
"text_name": "TNF"
},
{
"begin_idx": "643",
"end_idx": "646",
"entity_id": "7124",
"entity_type": "Gene",
"text_name": "TNF"
}
] | [
{
"begin_idx": "99",
"end_idx": "105",
"entity_id": "D018805",
"entity_type": "Disease",
"text_name": "sepsis"
},
{
"begin_idx": "30",
"end_idx": "45",
"entity_id": "D009369",
"entity_type": "Disease",
"text_name": "tumour necrosis"
}
] | [
"TNF",
"TNF"
] | [
"sepsis",
"tumour necrosis"
] |
8757036 | Late-onset GM2 gangliosidosis: Ashkenazi Jewish family with an exon 5 mutation (Tyr180-->His) in the Hex A alpha-chain gene. | Late-onset GM2 gangliosidosis is a variant form of Tay-Sachs disease characterized by onset of symptoms and signs in adolescence or in early adult life. The deficiency of beta-hexosaminidase A (Hex A) in this form of GM2 gangliosidosis has been invariably associated with the presence of the Gly269-->Ser substitution in the alpha-chain. We found two siblings of Ashkenazi Jewish descent diagnosed with late-onset GM2 gangliosidosis who were negative for the Gly269-->Ser mutation. Analysis of the HEXA gene showed that they were compound heterozygotes for the functionally silent 4-bp insertion in exon 11, typical of the infantile form of the disease and for a novel mutation, T538-->C, resulting in the missense Tyr180-->His. Expression studies in COS-7 cells suggested that the effect of this mutation was to decrease the stability of the alpha-chain at physiologic temperatures and therefore to indirectly affect the formation of mature Hex A. | [
{
"begin_idx": "176",
"end_idx": "193",
"entity_id": "D013661",
"entity_type": "Disease",
"text_name": "Tay-Sachs disease"
},
{
"begin_idx": "282",
"end_idx": "317",
"entity_id": "D013661",
"entity_type": "Disease",
"text_name": "deficiency of beta-hexosaminidase A"
},
... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "296",
"end_idx": "317",
"entity_id": "3073",
"entity_type": "Gene",
"text_name": "beta-hexosaminidase A"
},
{
"begin_idx": "623",
"end_idx": "627",
"entity_id": "3073",
"entity_type": "Gene",
"text_name": "HEXA"
}
] | [
{
"begin_idx": "282",
"end_idx": "317",
"entity_id": "D013661",
"entity_type": "Disease",
"text_name": "deficiency of beta-hexosaminidase A"
},
{
"begin_idx": "136",
"end_idx": "154",
"entity_id": "D020143",
"entity_type": "Disease",
"text_name": "GM2 gangliosidosis"
}
... | [
"beta-hexosaminidase A",
"HEXA"
] | [
"deficiency of beta-hexosaminidase A",
"GM2 gangliosidosis"
] |
8757758 | Clinicopathological correlations of compound heterozygous COL7A1 mutations in recessive dystrophic epidermolysis bullosa. | Recessive dystrophic epidermolysis bullosa is an inherited mechano-bullous disorder of skin and mucous membranes. Ultrastructurally, the disease is characterized by abnormalities of anchoring fibrils, attachment structures below the epidermal basement membrane, composed of type VII collagen. Mutations in the type VII collagen gene (COL7A1) have been shown conclusively to underlie dystrophic epidermolysis bullosa. Since there is variation of the phenotype, accompanied by heterogeneous anchoring fibril morphology and type VII collagen immunostaining, it is conceivable that different types and combinations of COL7A1 mutations correlate with different phenotypes. We therefore screened recessive dystrophic epidermolysis bullosa patients for COL7A1 mutations. Three unrelated patients showed the same premature termination codon mutation in exon 13 of one allele, yet they were all compound heterozygotes, each having a different mutation in the second allele. The first patient had a premature termination codon within the collagenous region of COL7A1 associated with severe disease, absent anchoring fibrils and undetectable type VII collagen immunostaining. The second had a premature termination codon in the non-collagenous NC-2 region associated with severe disease, wispy anchoring fibrils, and patchy type VII collagen immunostaining. The third had a glycine-to-aspartic acid substitution within the collagenous region, associated with milder disease, no identifiable anchoring fibrils, but near normal type VII collagen immunostaining. We conclude that the nature and position of mutations within COL7A1 correlate with specific disease features and may provide an insight into the molecular mechanisms of anchoring fibril formation and epidermal-dermal adhesion. | [
{
"begin_idx": "78",
"end_idx": "120",
"entity_id": "D016108",
"entity_type": "Disease",
"text_name": "recessive dystrophic epidermolysis bullosa"
},
{
"begin_idx": "122",
"end_idx": "164",
"entity_id": "D016108",
"entity_type": "Disease",
"text_name": "Recessive dystroph... | [
"Yes",
"No"
] | [
true,
false
] | [
{
"begin_idx": "58",
"end_idx": "64",
"entity_id": "1294",
"entity_type": "Gene",
"text_name": "COL7A1"
},
{
"begin_idx": "1732",
"end_idx": "1738",
"entity_id": "1294",
"entity_type": "Gene",
"text_name": "COL7A1"
}
] | [
{
"begin_idx": "78",
"end_idx": "120",
"entity_id": "D016108",
"entity_type": "Disease",
"text_name": "recessive dystrophic epidermolysis bullosa"
},
{
"begin_idx": "171",
"end_idx": "213",
"entity_id": "D030342",
"entity_type": "Disease",
"text_name": "inherited mechano-... | [
"COL7A1",
"COL7A1"
] | [
"recessive dystrophic epidermolysis bullosa",
"inherited mechano-bullous disorder of skin"
] |
8772692 | A meta-analysis of the association of the deletion allele of the angiotensin-converting enzyme gene with myocardial infarction. | BACKGROUND: The ACE gene is characterized by a polymorphism based on the presence (insertion [I]) or absence (deletion [D]) within intron 16 of a 287-basepair alu repeat sequence, resulting in three genotypes (DD and II homozygotes and ID heterozygotes). In 1992, the DD genotype was reported to be associated with an increased risk of myocardial infarction (MI). Subsequent studies have produced conflicting findings. To further evaluate the association of the ACE I/D genotype with MI risk, we carried out a meta-analysis of all the published studies. METHODS AND RESULTS: In total, 15 studies containing 3394 MI cases and 5479 control subjects were analyzed. The overall distribution of genotypes in the control subjects was 22.7% II, 49.0% ID, and 28.3% DD. The mean odds ratio for MI for DD versus ID/II genotypes across all studies was 1.26 (95% CI, 1.15, 1.39; P < .0001). Pairwise odds ratios were 1.36 (95% CI, 1.19, 1.55) for DD and II, 1.24 (95% CI, 1.11, 1.38) for DD and ID, and 1.09 (95% CI, 0.96, 1.23) for ID and II. The relative risk appeared to be increased in Japanese populations (2.55; 95% CI, 1.75, 3.70). CONCLUSIONS: Within the limitations of the available data, the meta-analysis therefore supports an association of the ACE D allele with MI risk and strengthens the justification for further evaluation in appropriately powered studies. | [
{
"begin_idx": "338",
"end_idx": "340",
"entity_id": "C536170",
"entity_type": "Disease",
"text_name": "DD"
},
{
"begin_idx": "396",
"end_idx": "398",
"entity_id": "C536170",
"entity_type": "Disease",
"text_name": "DD"
},
{
"begin_idx": "886",
"end_idx": "888"... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "144",
"end_idx": "147",
"entity_id": "1636",
"entity_type": "Gene",
"text_name": "ACE"
},
{
"begin_idx": "1374",
"end_idx": "1377",
"entity_id": "1636",
"entity_type": "Gene",
"text_name": "ACE"
}
] | [
{
"begin_idx": "105",
"end_idx": "126",
"entity_id": "D009203",
"entity_type": "Disease",
"text_name": "myocardial infarction"
},
{
"begin_idx": "886",
"end_idx": "888",
"entity_id": "C536170",
"entity_type": "Disease",
"text_name": "DD"
}
] | [
"ACE",
"ACE"
] | [
"myocardial infarction",
"DD"
] |
8772723 | A molecular variant of angiotensinogen is associated with diabetic nephropathy in IDDM. | Recent studies have suggested that an inherited predisposition to essential hypertension may increase susceptibility to nephropathy for patients with IDDM. Essential hypertension has been linked to the angiotensinogen (AGT) gene in genetic linkage studies in American and European populations. A molecular variant (M235T), which has a functional effect, has been described with highest plasma AGT levels being associated with the TT genotype. In a case-control study, we have evaluated the role of this functional genetic marker in patients with IDDM and nephropathy and in IDDM patients without nephropathy. We studied 195 IDDM patients, of whom 95 had established diabetic nephropathy; the remaining 100 patients, who had no evidence of microalbuminuria, served as control subjects. All patients were whites born in Northern Ireland. The point mutation in the AGT gene was analyzed using restriction typing. The background frequency of the M235T variant was assessed in 80 healthy blood donors, and the TT genotype was present in 9%. This genotype occurred in 8% of control IDDM patients without nephropathy and 19% of IDDM patients with nephropathy (P = 0.025). The odds ratio for diabetic nephropathy associated with the TT genotype was 2.7 (95% CI 1.04-7.52). There was no relationship between blood pressure and AGT genotypes in the control group. We cannot exclude the possibility that the observed association in the nephropathy group is due to an association between AGT genotype and hypertension. This evidence may help to explain the predisposition to diabetic nephropathy afforded by hypertension and merits further investigation. | [
{
"begin_idx": "82",
"end_idx": "86",
"entity_id": "D003922",
"entity_type": "Disease",
"text_name": "IDDM"
},
{
"begin_idx": "238",
"end_idx": "242",
"entity_id": "D003922",
"entity_type": "Disease",
"text_name": "IDDM"
},
{
"begin_idx": "634",
"end_idx": "63... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "23",
"end_idx": "38",
"entity_id": "183",
"entity_type": "Gene",
"text_name": "angiotensinogen"
},
{
"begin_idx": "290",
"end_idx": "305",
"entity_id": "183",
"entity_type": "Gene",
"text_name": "angiotensinogen"
}
] | [
{
"begin_idx": "82",
"end_idx": "86",
"entity_id": "D003922",
"entity_type": "Disease",
"text_name": "IDDM"
},
{
"begin_idx": "164",
"end_idx": "176",
"entity_id": "D006973",
"entity_type": "Disease",
"text_name": "hypertension"
}
] | [
"angiotensinogen",
"angiotensinogen"
] | [
"IDDM",
"hypertension"
] |
8774068 | Dexamethasone attenuates hypoglycemia in ten day old rats treated with TNF alpha. | Hypoglycemia during septic shock is a common and life-threatening sign in the newborn. TNF alpha is an important cytokine in endotoxic shock. The present study was performed to investigate if TNF alpha induces hypoglycemia and if dexamethasone ameliorates the TNF alpha effects in 10 day old rats. TNF alpha induced hypoglycemia and lactacidemia without altering plasma insulin concentration in 10 day old rats. TNF alpha increased GLUT1 mRNA abundance in brain, liver, muscle and fatty tissue, and decreased liver phosphoenolpyruvate carboxykinase (PEPCK) mRNA abundance. Dexamethasone attenuated the hypoglycemia and lactacidemia. Dexamethasone blunted the increase of GLUT1 mRNA abundance and increased the liver PEPCK mRNA abundance. Dexamethasone may be beneficial by promoting gluconeogenesis. | [
{
"begin_idx": "14",
"end_idx": "37",
"entity_id": "C538265",
"entity_type": "Disease",
"text_name": "attenuates hypoglycemia"
},
{
"begin_idx": "82",
"end_idx": "94",
"entity_id": "D007003",
"entity_type": "Disease",
"text_name": "Hypoglycemia"
},
{
"begin_idx": ... | [
"Yes",
"No"
] | [
true,
false
] | [
{
"begin_idx": "71",
"end_idx": "80",
"entity_id": "7124",
"entity_type": "Gene",
"text_name": "TNF alpha"
},
{
"begin_idx": "274",
"end_idx": "283",
"entity_id": "7124",
"entity_type": "Gene",
"text_name": "TNF alpha"
}
] | [
{
"begin_idx": "82",
"end_idx": "94",
"entity_id": "D007003",
"entity_type": "Disease",
"text_name": "Hypoglycemia"
},
{
"begin_idx": "102",
"end_idx": "114",
"entity_id": "D012772",
"entity_type": "Disease",
"text_name": "septic shock"
}
] | [
"TNF alpha",
"TNF alpha"
] | [
"Hypoglycemia",
"septic shock"
] |
8778602 | Premature atherosclerosis in patients with familial chylomicronemia caused by mutations in the lipoprotein lipase gene. | BACKGROUND: Patients with lipoprotein lipase deficiency usually present with chylomicronemia in childhood. The syndrome has been considered nonatherogenic primarily because of the low levels of low-density lipoprotein (LDL) cholesterol. We prospectively evaluated patients with lipoprotein lipase deficiency for atherosclerosis. METHODS: Evidence of carotid, peripheral, and coronary atherosclerosis was sought in four patients (two men and two women) with the phenotype of familial chylomicronemia by clinical examination over a period of 14 to 30 years and by Doppler ultrasonography, B-mode ultrasonography [corrected], and exercise-tolerance testing after the age of 40. Angiography was performed when indicated. Lipoprotein lipase deficiency was assessed in vivo and in vitro by functional assays and DNA-sequence analysis. RESULTS: All four patients had a profound functional deficiency of lipoprotein lipase with a reduced enzymatic mass due to missense mutations on both alleles of the lipoprotein lipase gene. In all four patients, peripheral or coronary atherosclerosis (or both) was observed before the age of 55. Despite following a low-fat diet in which fat composed 10 to 15 percent of the daily caloric intake, the patients had hypertriglyceridemia (mean [+/- SD] triglyceride level, 2621 +/- 1112 mg per deciliter [29.59 +/- 12.55 mmol per liter]), low plasma levels of high-density lipoprotein cholesterol (17 +/- 7 mg per deciliter [0.43 +/- 0.18 mmol per liter]), and very low levels of LDL cholesterol (28 +/- 16 mg per deciliter [0.72 +/- 0.41 mmol per liter]). Three patients had one risk factor for atherosclerosis, whereas in one male patient, heavy smoking and diabetes were associated with an accelerated course of the disease. CONCLUSIONS: Premature atherosclerosis can occur in patients with familiar chylomicronemia as a result of mutations in the lipoprotein lipase gene. Defective lipolysis may increase susceptibility to atherosclerosis in humans. | [
{
"begin_idx": "495",
"end_idx": "519",
"entity_id": "D003324",
"entity_type": "Disease",
"text_name": "coronary atherosclerosis"
},
{
"begin_idx": "1175",
"end_idx": "1199",
"entity_id": "D003324",
"entity_type": "Disease",
"text_name": "coronary atherosclerosis"
},
... | [
"Yes",
"No"
] | [
true,
false
] | [
{
"begin_idx": "95",
"end_idx": "113",
"entity_id": "4023",
"entity_type": "Gene",
"text_name": "lipoprotein lipase"
},
{
"begin_idx": "1997",
"end_idx": "2015",
"entity_id": "4023",
"entity_type": "Gene",
"text_name": "lipoprotein lipase"
}
] | [
{
"begin_idx": "1002",
"end_idx": "1034",
"entity_id": "D008072",
"entity_type": "Disease",
"text_name": "deficiency of lipoprotein lipase"
},
{
"begin_idx": "1806",
"end_idx": "1814",
"entity_id": "D003920",
"entity_type": "Disease",
"text_name": "diabetes"
}
] | [
"lipoprotein lipase",
"lipoprotein lipase"
] | [
"deficiency of lipoprotein lipase",
"diabetes"
] |
8782832 | Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures. | Among the diverse family of collagens, the widely expressed microfibrillar type VI collagen is believed to play a role in bridging cells with the extracellular matrix. Several observations imply substrate properties for cell attachment as well as association with major collagen fibers. Previously, we have established genetic linkage between the genes encoding the three constituent alpha-chains of type VI collagen and Bethlem myopathy. A distinctive feature of this autosomal dominant disorder consists of contractures of multiple joints in addition to generalized muscular weakness and wasting. Nine kindreds show genetic linkage to the COL6A1-COL6A2 cluster on chromosome 21q22.3 (refs 3,4; manuscript submitted) whereas one family shows linkage to markers on chromosome 2q37 close to COL6A3 (ref. 5). Sequence analysis in four families reveals a mutation in COL6A1 in one and a COL6A2 mutation in two other kindreds. Both mutations disrupt the Gly-X-Y motif of the triple helical domain by substitution of Gly for either Val or Ser. Analogous to the putative perturbation of the anchoring function of the dystrophin-associated complex in congenital muscular dystrophy with mutations in the alpha 2-subunit of laminin, our observations suggest a similar mechanism in Bethlem myopathy. | [
{
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"end_idx": "46",
"entity_id": "C535436",
"entity_type": "Disease",
"text_name": "Bethlem myopathy"
},
{
"begin_idx": "519",
"end_idx": "535",
"entity_id": "C535436",
"entity_type": "Disease",
"text_name": "Bethlem myopathy"
},
{
"begin_idx": "... | [
"Yes",
"Yes",
"No",
"No"
] | [
false,
false,
false,
false
] | [
{
"begin_idx": "746",
"end_idx": "752",
"entity_id": "1292",
"entity_type": "Gene",
"text_name": "COL6A2"
},
{
"begin_idx": "739",
"end_idx": "745",
"entity_id": "1291",
"entity_type": "Gene",
"text_name": "COL6A1"
},
{
"begin_idx": "888",
"end_idx": "894",
... | [
{
"begin_idx": "30",
"end_idx": "46",
"entity_id": "C535436",
"entity_type": "Disease",
"text_name": "Bethlem myopathy"
},
{
"begin_idx": "30",
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"entity_id": "C535436",
"entity_type": "Disease",
"text_name": "Bethlem myopathy"
},
{
"begin_idx": "84... | [
"COL6A2",
"COL6A1",
"COL6A3",
"COL6A2"
] | [
"Bethlem myopathy",
"Bethlem myopathy",
"contractures",
"autosomal dominant disorder"
] |
8786069 | Two different mutations are responsible for Krabbe disease in the Druze and Moslem Arab populations in Israel. | Infantile Krabbe disease is a severe, fatal autosomal recessive disorder resulting from the deficiency of galactocerebrosidase (GALC) activity. It is relatively common in two separate inbred communities in Israel. In the Druze community in Northern Israel and two Moslem Arab villages located near Jerusalem the incidence of Krabbe disease is about 1 in 100-150 live births. With our cloning of the GALC gene, mutation analysis of these populations was undertaken. The Moslem Arabs were homozygous for two mutations in the GALC gene; a T-to-C transition at CDNA position 1637 (counting from the A of the initiation codon), which is considered a polymorphism and a G-to-A transition at position 1582, which changes the codon for aspartic acid to one for asparagine. The Druze patients are homozygous for a T-to-G transversion at position 1748, which changes the codon for isoleucine to one for serine. Expression studies confirmed the deleterious nature of these mutations. The development of a simple polymerase chain reaction (PCR) amplification and restriction enzyme digestion method to identify these alleles will lead to accurate carrier testing and improved genetic counseling for interested individuals in these communities. | [
{
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"end_idx": "58",
"entity_id": "D007965",
"entity_type": "Disease",
"text_name": "Krabbe disease"
},
{
"begin_idx": "111",
"end_idx": "135",
"entity_id": "D007965",
"entity_type": "Disease",
"text_name": "Infantile Krabbe disease"
},
{
"begin_i... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "217",
"end_idx": "237",
"entity_id": "2581",
"entity_type": "Gene",
"text_name": "galactocerebrosidase"
},
{
"begin_idx": "239",
"end_idx": "243",
"entity_id": "2581",
"entity_type": "Gene",
"text_name": "GALC"
}
] | [
{
"begin_idx": "203",
"end_idx": "237",
"entity_id": "D007965",
"entity_type": "Disease",
"text_name": "deficiency of galactocerebrosidase"
},
{
"begin_idx": "155",
"end_idx": "183",
"entity_id": "D030342",
"entity_type": "Disease",
"text_name": "autosomal recessive disor... | [
"galactocerebrosidase",
"GALC"
] | [
"deficiency of galactocerebrosidase",
"autosomal recessive disorder"
] |
8794836 | Genetic association of 11 beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) flanking microsatellites with essential hypertension in blacks. | 11 beta-Hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) specifically modulates access of the mineralocorticoid aldosterone to the kidney mineralocorticoid type 1 receptors in a physiological environment in which there is a molar excess of cortisol. Cortisol and aldosterone have similar affinities for mineralocorticoid receptors. Mechanistically, 11 beta-HSD2 converts cortisol to cortisone. The other known isoform, 11 beta-HSD1, not only catalyzes the cortisol to cortisone reaction but also the reverse reaction, making it unlikely to play an important role in modulating the access of aldosterone to mineralocorticoid receptors. Mutations in the HSD11B2 gene (both exonic and intronic) have been demonstrated to cause reduced activity of this enzyme in the syndrome of apparent mineralocorticoid excess, a rare autosomal recessive disorder. We hypothesized that this locus is also involved in the etiology of essential hypertension. To test this locus and flanking chromosomal regions for allelic association and genetic linkage to essential hypertension, it is necessary to have informative genetic markers. To this end, we have refined the localization of 11 beta-HSD2 to 16q22.1. We genotyped subjects using the nearest flanking microsatellites (D16S301 and D16S496). We conducted an association study using black subjects with hypertensive end-stage renal disease, black normotensive control subjects, and black and white individuals from the general population. We used chi 2 analysis and Fisher's exact test to test for association with these candidate gene markers. No significant association was found between D16S301 and hypertension. However, a positive association with hypertension was found at the D16S496 microsatellite locus (chi 2 = 6.98, df = 1, P < or = .008). Our data suggest that HSD11B2 is associated with hypertension in our black subjects with hypertensive end-stage renal disease. The 16q22.1 chromosome region potentially harbors a candidate gene for essential hypertension. Confirmation of our findings in another independently ascertained group of hypertensive subjects will provide a basis for proceeding with sib-pair linkage analyses. | [
{
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"end_idx": "129",
"entity_id": "D006973",
"entity_type": "Disease",
"text_name": "hypertension"
},
{
"begin_idx": "1068",
"end_idx": "1080",
"entity_id": "D006973",
"entity_type": "Disease",
"text_name": "hypertension"
},
{
"begin_idx": "1191... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "186",
"end_idx": "198",
"entity_id": "3291",
"entity_type": "Gene",
"text_name": "11 beta-HSD2"
},
{
"begin_idx": "186",
"end_idx": "198",
"entity_id": "3291",
"entity_type": "Gene",
"text_name": "11 beta-HSD2"
}
] | [
{
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"end_idx": "129",
"entity_id": "D006973",
"entity_type": "Disease",
"text_name": "hypertension"
},
{
"begin_idx": "1493",
"end_idx": "1516",
"entity_id": "D007676",
"entity_type": "Disease",
"text_name": "end-stage renal disease"
}
] | [
"11 beta-HSD2",
"11 beta-HSD2"
] | [
"hypertension",
"end-stage renal disease"
] |
8807342 | Complete deficiency of plasma lecithin-cholesterol acyltransferase (LCAT) activity due to a novel homozygous mutation (Gly-30-Ser) in the LCAT gene. | [
{
"begin_idx": "0",
"end_idx": "82",
"entity_id": "D007863",
"entity_type": "Disease",
"text_name": "Complete deficiency of plasma lecithin-cholesterol acyltransferase (LCAT) activity"
},
{
"begin_idx": "68",
"end_idx": "72",
"entity_id": "3931",
"entity_type": "Gene",
"t... | [
"Yes"
] | [
true
] | [
{
"begin_idx": "68",
"end_idx": "72",
"entity_id": "3931",
"entity_type": "Gene",
"text_name": "LCAT"
}
] | [
{
"begin_idx": "0",
"end_idx": "82",
"entity_id": "D007863",
"entity_type": "Disease",
"text_name": "Complete deficiency of plasma lecithin-cholesterol acyltransferase (LCAT) activity"
}
] | [
"LCAT"
] | [
"Complete deficiency of plasma lecithin-cholesterol acyltransferase (LCAT) activity"
] | |
8821841 | Genetic risk for renal artery stenosis: association with deletion polymorphism in angiotensin 1-converting enzyme gene. | Atherosclerotic renal artery disease is an important secondary cause of hypertension. Currently, there is great interest in possible genetic determinants of cardiovascular disease. The ACE-D allele has been reported to be associated with increased risk of myocardial infarction as well as coronary re-stenosis after angioplasty. We therefore assessed whether this allele is also linked to renovascular disease by studying 56 Caucasian subjects with atherosclerotic renal artery stenosis and 74 age, sex and race matched control subjects. Genetic analysis for the ACE I/D polymorphism was performed on peripheral leukocytes using PCR techniques, including insertion-specific primers. The distribution of I and D alleles was: renal artery stenosis 8 II, 25 ID, 23 DD; and controls, 16 II, 41 ID, 17 DD. The frequency of the D allele in the renal artery stenosis group was significantly higher (D/total 71/112 = 0.66) than that of the control population [75/148 = 0.51; chi 2 = 4.17, P = 0.04; odds ratio 1.69 (95% CI 1.02 to 2.78)]. Our results suggest that the ACE-D allele may be associated with increased risk of vascular disease at sites other than the coronary circulation. | [
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"end_idx": "884",
"entity_id": "C536170",
"entity_type": "Disease",
"text_name": "DD"
},
{
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"end_idx": "919",
"entity_id": "C536170",
"entity_type": "Disease",
"text_name": "DD"
},
{
"begin_idx": "277",
"end_idx": "299"... | [
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] | [
false,
true
] | [
{
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"text_name": "ACE"
},
{
"begin_idx": "305",
"end_idx": "308",
"entity_id": "1636",
"entity_type": "Gene",
"text_name": "ACE"
}
] | [
{
"begin_idx": "569",
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"entity_id": "D012078",
"entity_type": "Disease",
"text_name": "atherosclerotic renal artery stenosis"
},
{
"begin_idx": "1234",
"end_idx": "1250",
"entity_id": "D014652",
"entity_type": "Disease",
"text_name": "vascular disease"
... | [
"ACE",
"ACE"
] | [
"atherosclerotic renal artery stenosis",
"vascular disease"
] |
8823764 | Allelic association analysis of the 5-HT2C receptor gene in bipolar affective disorder. | We have examined a structural variant of the 5-HT2C receptor (Cys23Ser) for allelic association with bipolar affective disorder in 88 cases and 113 controls. Overall, there was no significant difference in allele frequencies between the two groups, indicating that the 5-HT2C gene is not a major risk factor for bipolar affective disorder. However, when the subjects were analysed according to sex, there was a small excess of the serine ser23 allele in female cases (P = 0.04) and this effect was also seen if the ser23 allele was considered recessive (P = 0.03). A small increase in significance was found if only female cases with a known family history were included (P = 0.01). These results suggest that the ser23 allele may increase susceptibility to bipolar affective disorder in women. | [
{
"begin_idx": "60",
"end_idx": "86",
"entity_id": "D001714",
"entity_type": "Disease",
"text_name": "bipolar affective disorder"
},
{
"begin_idx": "189",
"end_idx": "215",
"entity_id": "D001714",
"entity_type": "Disease",
"text_name": "bipolar affective disorder"
},
... | [
"Yes"
] | [
true
] | [
{
"begin_idx": "36",
"end_idx": "42",
"entity_id": "3358",
"entity_type": "Gene",
"text_name": "5-HT2C"
}
] | [
{
"begin_idx": "60",
"end_idx": "86",
"entity_id": "D001714",
"entity_type": "Disease",
"text_name": "bipolar affective disorder"
}
] | [
"5-HT2C"
] | [
"bipolar affective disorder"
] |
8825899 | Association analysis of a polymorphism of the monoamine oxidase B gene with Parkinson's disease in a Japanese population. | The polymorphic allele of the monoamine oxidase B (MAO-B) gene detected by polymerase chain reaction (PCR) and single-stranded conformation polymorphism (SSCP) was associated with Parkinson's disease (PD) in Caucasians. We characterized this polymorphic allele, allele 1, of the MAO-B gene using direct sequencing of PCR products. A single DNA substitution (G-A), resulting gain of Mae III restriction site was detected in intron 13 of the MAO-B gene. The allele associated with PD in Caucasians was twice as frequent as in healthy Japanese, but the association of the allele of the MAO-B gene was not observed in Japanese patients with PD. | [
{
"begin_idx": "76",
"end_idx": "95",
"entity_id": "D010300",
"entity_type": "Disease",
"text_name": "Parkinson's disease"
},
{
"begin_idx": "302",
"end_idx": "321",
"entity_id": "D010300",
"entity_type": "Disease",
"text_name": "Parkinson's disease"
},
{
"begin_i... | [
"Yes"
] | [
true
] | [
{
"begin_idx": "46",
"end_idx": "65",
"entity_id": "4129",
"entity_type": "Gene",
"text_name": "monoamine oxidase B"
}
] | [
{
"begin_idx": "76",
"end_idx": "95",
"entity_id": "D010300",
"entity_type": "Disease",
"text_name": "Parkinson's disease"
}
] | [
"monoamine oxidase B"
] | [
"Parkinson's disease"
] |
8825918 | Mutations in the RET proto-oncogene and the von Hippel-Lindau disease tumour suppressor gene in sporadic and syndromic phaeochromocytomas. | Phaeochromocytomas may occur sporadically, or as part of the inherited cancer syndromes multiple endocrine neoplasia (MEN) type 2, von Hippel-Lindau disease (VHL), and, rarely, in type 1 neurofibromatosis. In MEN 2, germline missense mutations have been found in one of eight codons within exons 10, 11, 13, 14, and 16 of the RET proto-oncogene. In VHL, germline mutations within one of the three exons are responsible for the majority of cases. To determine if somatic mutations similar to those seen in the germline in MEN 2 or VHL disease play a role in the pathogenesis of sporadic or familial phaeochromocytomas, we analysed 48 sporadic tumours and tumours from 17 MEN 2 and five VHL patients for mutations in RET exons 9, 10, 11, 13, 14, 15, and 16, and the entire coding sequence of VHL. Five of 48 sporadic phaeochromocytomas had RET mutations within exons 10, 11, and 16. Of these, one was proven to be germline and two were proven to be somatic mutations. Four of 48 had VHL mutations; these included both the bilateral cases in the series (one was proven to be a germline mutation) and two others, of which one was proven somatic. | [
{
"begin_idx": "44",
"end_idx": "76",
"entity_id": "D006623",
"entity_type": "Disease",
"text_name": "von Hippel-Lindau disease tumour"
},
{
"begin_idx": "270",
"end_idx": "295",
"entity_id": "D006623",
"entity_type": "Disease",
"text_name": "von Hippel-Lindau disease"
... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "270",
"end_idx": "295",
"entity_id": "7428",
"entity_type": "Gene",
"text_name": "von Hippel-Lindau disease"
},
{
"begin_idx": "1120",
"end_idx": "1123",
"entity_id": "7428",
"entity_type": "Gene",
"text_name": "VHL"
}
] | [
{
"begin_idx": "44",
"end_idx": "76",
"entity_id": "D006623",
"entity_type": "Disease",
"text_name": "von Hippel-Lindau disease tumour"
},
{
"begin_idx": "772",
"end_idx": "788",
"entity_id": "D009369",
"entity_type": "Disease",
"text_name": "sporadic tumours"
}
] | [
"von Hippel-Lindau disease",
"VHL"
] | [
"von Hippel-Lindau disease tumour",
"sporadic tumours"
] |
8834236 | Mutations of the Btk gene in 12 unrelated families with X-linked agammaglobulinemia in Japan. | Alterations of the Bruton's tyrosine kinase (Btk) gene are responsible for X-linked agammaglobulinemia (XLA). Although mutations in various regions were reported mainly in the Caucasian population, correlation between the locations of mutation and the clinical phenotypes remains unclear. We report 12 abnormalities of the Btk gene found in 12 unrelated families out of 14 XLA families in Japan and their clinical features. We utilized Southern blotting and single-strand conformation polymorphism (SSCP) analysis. Gene rearrangement in the kinase domain was identified in two patients by Southern blotting. Seven point mutations, two small deletions, and one small insertion were detected by SSCP and sequencing. The SSCP analysis also provided information about the carriers in these families. We found some clinical heterogeneity in the affected family members with the same gene mutation. Moreover, there is considerable inconsistency between the locations of gene aberrations and the immunological phenotypes. Some patients with a nonsense mutation, which may result in the lack of kinase domain, have detectable B cells and immunoglobulins. These identified alterations will provide valuable clues to the Btk protein function and the pathogenesis of XLA. | [
{
"begin_idx": "56",
"end_idx": "83",
"entity_id": "C537409",
"entity_type": "Disease",
"text_name": "X-linked agammaglobulinemia"
},
{
"begin_idx": "169",
"end_idx": "196",
"entity_id": "C537409",
"entity_type": "Disease",
"text_name": "X-linked agammaglobulinemia"
},
... | [
"Yes"
] | [
true
] | [
{
"begin_idx": "113",
"end_idx": "137",
"entity_id": "695",
"entity_type": "Gene",
"text_name": "Bruton's tyrosine kinase"
}
] | [
{
"begin_idx": "56",
"end_idx": "83",
"entity_id": "C537409",
"entity_type": "Disease",
"text_name": "X-linked agammaglobulinemia"
}
] | [
"Bruton's tyrosine kinase"
] | [
"X-linked agammaglobulinemia"
] |
8840969 | Mutations in the human homologue of the Drosophila patched gene in Caucasian and African-American nevoid basal cell carcinoma syndrome patients. | The nevoid basal cell carcinoma syndrome (NBCCS), or Gorlin syndrome, is a multisystem autosomal dominant disorder. The salient features of this syndrome include multiple basal cell carcinomas, palmar and/or plantar pits, odontogenic keratocysts, skeletal and developmental anomalies, and ectopic calcification. Other features include such tumors as ovarian fibromas and medulloblastomas. There is extensive interfamilial as well as intrafamilial variability with respect to the manifestation and severity of the phenotype. Alterations in the human homologue (PTCH) of the Drosophila segment polarity gene patched have been identified in NBCCS patients as well as tumors associated with this syndrome. We report several mutations in this gene in NBCCS patients and present the clinical phenotypes of the individuals in whom these mutations were identified. | [
{
"begin_idx": "339",
"end_idx": "365",
"entity_id": "C536528",
"entity_type": "Disease",
"text_name": "palmar and/or plantar pits"
},
{
"begin_idx": "367",
"end_idx": "428",
"entity_id": "D000014",
"entity_type": "Disease",
"text_name": "odontogenic keratocysts, skeletal... | [
"Yes",
"No"
] | [
false,
false
] | [
{
"begin_idx": "51",
"end_idx": "58",
"entity_id": "5727",
"entity_type": "Gene",
"text_name": "patched"
},
{
"begin_idx": "51",
"end_idx": "58",
"entity_id": "5727",
"entity_type": "Gene",
"text_name": "patched"
}
] | [
{
"begin_idx": "198",
"end_idx": "213",
"entity_id": "D001478",
"entity_type": "Disease",
"text_name": "Gorlin syndrome"
},
{
"begin_idx": "339",
"end_idx": "365",
"entity_id": "C536528",
"entity_type": "Disease",
"text_name": "palmar and/or plantar pits"
}
] | [
"patched",
"patched"
] | [
"Gorlin syndrome",
"palmar and/or plantar pits"
] |
8843235 | Variation in the tumor necrosis factor-alpha gene promoter region may be associated with death from meningococcal disease. | Tumor necrosis factor-alpha (TNF-alpha) plays a central role in the pathophysiology of sepsis. Levels of TNF-alpha are directly correlated with severity in meningococcal disease (MD). A polymorphism in the promoter region of the TNF-alpha gene is associated with differences in the secretion of TNF-alpha. The TNF2 allele is associated with higher constitutive and inducible levels of TNF-alpha secretion than is the TNF1 allele. To investigate whether possession of the TNF2 allele is associated with severity in MD, the frequency of TNF1 and TNF2 alleles in 98 children with MD was compared. There were more deaths among children who had the TNF2 allele (P = .03; relative risk [RR], 2.5; 95% confidence interval [CI], 1.1-5.7) than in those who did not. There was also an increased risk of severe disease in children with the TNF2 allele (P = .02; RR, 1.6; 95% CI, 1.1-2.3). Possession of the TNF2 allele predisposes to a worse outcome in children with meningococcal infection. | [
{
"begin_idx": "89",
"end_idx": "94",
"entity_id": "D003643",
"entity_type": "Disease",
"text_name": "death"
},
{
"begin_idx": "100",
"end_idx": "121",
"entity_id": "D008589",
"entity_type": "Disease",
"text_name": "meningococcal disease"
},
{
"begin_idx": "279",
... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "17",
"end_idx": "44",
"entity_id": "7124",
"entity_type": "Gene",
"text_name": "tumor necrosis factor-alpha"
},
{
"begin_idx": "228",
"end_idx": "237",
"entity_id": "7124",
"entity_type": "Gene",
"text_name": "TNF-alpha"
}
] | [
{
"begin_idx": "1079",
"end_idx": "1102",
"entity_id": "D008589",
"entity_type": "Disease",
"text_name": "meningococcal infection"
},
{
"begin_idx": "89",
"end_idx": "94",
"entity_id": "D003643",
"entity_type": "Disease",
"text_name": "death"
}
] | [
"tumor necrosis factor-alpha",
"TNF-alpha"
] | [
"meningococcal infection",
"death"
] |
8852666 | Dopa-responsive dystonia in British patients: new mutations of the GTP-cyclohydrolase I gene and evidence for genetic heterogeneity. | Dopa-responsive dystonia (DRD) was originally described in a series of Japanese patients, but is now increasingly recognized in other countries. Recently the GTP cyclohydrolase I (GTPCH) gene was isolated as the first causative gene for dopa-responsive dystonia (DRD). Mutations were identified in three Japanese families with autosomal dominantly inherited DRD and in one sporadic Japanese patient. Characterisation of the exon-intron boundaries of this gene has now allowed the analysis of mutations at the level of genomic DNA. Amplifying all six exons, we analyzed the GTPCH gene in nine British families with 33 affected family members and in three sporadic cases and found six new mutations. Only point mutations were found, causing a stop codon in one family and an amino acid change in highly conserved regions of the gene in a further four families and in one sporadic case. None of these mutations were detected more than once and none of the mutations previously described were found in our patients. No mutations were identified in four families and in two sporadic cases. | [
{
"begin_idx": "0",
"end_idx": "24",
"entity_id": "C538007",
"entity_type": "Disease",
"text_name": "Dopa-responsive dystonia"
},
{
"begin_idx": "133",
"end_idx": "157",
"entity_id": "C538007",
"entity_type": "Disease",
"text_name": "Dopa-responsive dystonia"
},
{
... | [
"Yes",
"No"
] | [
true,
false
] | [
{
"begin_idx": "67",
"end_idx": "87",
"entity_id": "2643",
"entity_type": "Gene",
"text_name": "GTP-cyclohydrolase I"
},
{
"begin_idx": "313",
"end_idx": "318",
"entity_id": "2643",
"entity_type": "Gene",
"text_name": "GTPCH"
}
] | [
{
"begin_idx": "0",
"end_idx": "24",
"entity_id": "C538007",
"entity_type": "Disease",
"text_name": "Dopa-responsive dystonia"
},
{
"begin_idx": "460",
"end_idx": "494",
"entity_id": "D030342",
"entity_type": "Disease",
"text_name": "autosomal dominantly inherited DRD"
... | [
"GTP-cyclohydrolase I",
"GTPCH"
] | [
"Dopa-responsive dystonia",
"autosomal dominantly inherited DRD"
] |
8866423 | Enhanced superoxide dismutase-2 immunoreactivity of astrocytes and occasional neurons in amyotrophic lateral sclerosis. | The recent discovery of missense mutations in the superoxide dismutase (SOD)-1 gene as a cause of familial amyotrophic lateral sclerosis (ALS) and the ensuing description of transgenic SOD-1 mutant mouse models have focussed scientific interest on free radical scavenging mechanisms in all other familial (FALS) and sporadic (SALS) forms of the disease. We have compared the presence of intracellular cytosolic copper-zinc SOD-1 and mitochondrial manganese SOD-2 in the CNS from FALS and SALS patients and from non-neurological controls by immunohistochemical assessment, in the knowledge that no SOD-1 mutations have been found in any of 18 Dutch ALS pedigrees. ALS specimens from the motor cortex and the spinal cord presented enhanced SOD-2 immunoreactivity, especially of astrocytes and occasionally of neurons. Astrocyte staining appeared to be increased at the cerebral cortical and the spinal cervical and lumbar levels, but was only slightly increased in the thoracic anterior horns and not at all in the brain stem. This indicates that, by the time of death, the disease had burnt out in the brain stem and thoracic cord. Increased staining of neurons was limited to the small lateral and dorsal nuclei of the spinal cord. FALS and SALS cases exhibited the same staining patterns. SOD-1 immunoreactivity did not differ between disease and control specimens. SOD-1 and -2 staining was normal in the ALS cortical, brain stem and spinal motoneurons. This suggests that SALS and non-SOD-1 mutant FALS are not accompanied by loss of SOD-1 or -2 protein. An enzyme-linked immunosorbent assay revealed no differences in SOD-1 and SOD-2 levels between ALS patients and controls. Our major finding of locally increased SOD-2 immunoreactivity of astrocytes in FALS and SALS specimens, probably reflects reactive fibrillary and protoplasmatic gliosis in areas of ongoing degeneration but may also result from an attempt at compensation for free radical injury. | [
{
"begin_idx": "218",
"end_idx": "256",
"entity_id": "C531617",
"entity_type": "Disease",
"text_name": "familial amyotrophic lateral sclerosis"
},
{
"begin_idx": "426",
"end_idx": "430",
"entity_id": "C531617",
"entity_type": "Disease",
"text_name": "FALS"
},
{
"b... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "1487",
"end_idx": "1499",
"entity_id": "6648",
"entity_type": "Gene",
"text_name": "SOD-1 and -2"
},
{
"begin_idx": "1410",
"end_idx": "1415",
"entity_id": "6647",
"entity_type": "Gene",
"text_name": "SOD-1"
}
] | [
{
"begin_idx": "89",
"end_idx": "118",
"entity_id": "D000690",
"entity_type": "Disease",
"text_name": "amyotrophic lateral sclerosis"
},
{
"begin_idx": "218",
"end_idx": "256",
"entity_id": "C531617",
"entity_type": "Disease",
"text_name": "familial amyotrophic lateral sc... | [
"SOD-1 and -2",
"SOD-1"
] | [
"amyotrophic lateral sclerosis",
"familial amyotrophic lateral sclerosis"
] |
8879960 | Absence of the Gly40-ser mutation in the glucagon receptor gene in Japanese subjects with NIDDM. | Recent studies have shown both association and linkage between a Gly40-Ser mutation in the glucagon receptor gene and NIDDM in French patients with familial NIDDM. This mutation was present in heterozygous form in 4.6% of diabetic probands but only 1% of the French population, suggesting that it was an important risk factor in the development of NIDDM. A total of 348 unrelated Japanese subjects (220 with NIDDM, 53 with impaired glucose tolerance (IGT) and 75 normal subjects) were screened for the presence of the Gly40-Ser mutation. Seventy-two percent of the NIDDM patients and 52% of IGT subjects had a positive family history of NIDDM. The Gly40-Ser mutation, which could be readily detected in a positive control subject, was not found in any of the 348 Japanese subjects studied. Thus, the Gly40-Ser mutation does not play an important role in the pathogenesis of NIDDM in Japanese patients. | [
{
"begin_idx": "319",
"end_idx": "327",
"entity_id": "D003920",
"entity_type": "Disease",
"text_name": "diabetic"
},
{
"begin_idx": "90",
"end_idx": "95",
"entity_id": "D003924",
"entity_type": "Disease",
"text_name": "NIDDM"
},
{
"begin_idx": "215",
"end_idx"... | [
"Yes",
"No"
] | [
true,
false
] | [
{
"begin_idx": "41",
"end_idx": "58",
"entity_id": "2642",
"entity_type": "Gene",
"text_name": "glucagon receptor"
},
{
"begin_idx": "41",
"end_idx": "58",
"entity_id": "2642",
"entity_type": "Gene",
"text_name": "glucagon receptor"
}
] | [
{
"begin_idx": "245",
"end_idx": "259",
"entity_id": "D003924",
"entity_type": "Disease",
"text_name": "familial NIDDM"
},
{
"begin_idx": "548",
"end_idx": "551",
"entity_id": "D018149",
"entity_type": "Disease",
"text_name": "IGT"
}
] | [
"glucagon receptor",
"glucagon receptor"
] | [
"familial NIDDM",
"IGT"
] |
8889583 | PKU mutation (D143G) associated with an apparent high residual enzyme activity: expression of a kinetic variant form of phenylalanine hydroxylase in three different systems. | We have used three complementary in vitro systems to express the human phenylalanine hydroxylase (PAH) gene at high levels. Recombinant PAH was expressed in Escherichia coli (as a fusion protein), in human kidney cells and in a cell-free in vitro transcription-translation system. These systems were used to characterize a novel kinetic variant form (D143G) of the enzyme. The recombinant D143G mutant enzyme had the same physicochemical properties as the wild-type PAH and was stable when expressed in eukaryotic cells. Enzyme activity studies of the D143G mutant enzyme, produced in the three expression systems, revealed a kinetic variant form with reduced affinity for L-Phe (about 2.4-fold increase in the S0.5 value) as well as reduced affinity for tetrahydrobiopterin (BH4) (about 2-fold increase in the apparent Km). At standard assay conditions (1 mM L-Phe, t5 microM BH4) the residual activity of the mutant enzyme was high and variable (52%, 33%, and 102%) when analysed in the three different systems. The high residual activities of the mutant enzyme obtained at these conditions were not in agreement with the classical PKU phenotype found in a patient compound heterozygous for the termination mutation G272X and the novel D143G mutation. However, when the D143G mutant enzyme was assayed at lower concentrations of L-Phe (100-300 microM) and BH4 (10 microM) the residual activities were compatible with severely reduced hydroxylation of L-Phe and the classical PKU phenotype. | [
{
"begin_idx": "0",
"end_idx": "3",
"entity_id": "D010661",
"entity_type": "Disease",
"text_name": "PKU"
},
{
"begin_idx": "1308",
"end_idx": "1311",
"entity_id": "D010661",
"entity_type": "Disease",
"text_name": "PKU"
},
{
"begin_idx": "1651",
"end_idx": "165... | [
"Yes"
] | [
true
] | [
{
"begin_idx": "120",
"end_idx": "145",
"entity_id": "5053",
"entity_type": "Gene",
"text_name": "phenylalanine hydroxylase"
}
] | [
{
"begin_idx": "0",
"end_idx": "3",
"entity_id": "D010661",
"entity_type": "Disease",
"text_name": "PKU"
}
] | [
"phenylalanine hydroxylase"
] | [
"PKU"
] |
8896428 | Five new mutations in the uroporphyrinogen decarboxylase gene identified in families with cutaneous porphyria. | We describe five new mutations in the uroporphyrinogen decarboxylase (UROD) gene. All mutations were observed in conjunction with decreased erythrocyte UROD and clinical familial porphyria cutanea tarda (fPCT), (four families) or hepatoerythropoietic porphyria (HEP), (one family). The fPCT mutations included three point mutations that resulted in amino acid substitutions: a lysine to glutamine at amino acid position 253 (exon 7); a glycine to arginine at position 318 (exon 10); an isoleucine to threonine at position 334 (exon 10). The lysine to glutamine at amino acid position 253 was found in conjunction with a single C nucleotide deletion in exon 8 on the same allele of the UROD gene in the same family. This deletion resulted in a shift in the reading frame and the introduction of a premature stop codon 8 amino acids downstream. In the fourth family, a 31-bp deletion (nucleotides 828-858: exon 8) of the coding region, resulted in a frameshift and the introduction of a stop codon 19 amino acids downstream. A point mutation was observed in an individual diagnosed with HEP, resulting in an alanine to glycine change at amino acid position 80 and was present on both alleles. All mutations were confirmed in at least one other family member. The impact of these mutations on the function of the UROD protein was examined using in vitro protein expression and with activity assessed using pentacarboxylic acid porphyrinogen I as a substrate for UROD. Although three mutations reduced UROD activity to < 15% of normal, one resulted in a UROD protein with 50% functional activity and the other had near normal activity. These results indicate that many different genetic lesions of the UROD gene are associated with fPCT. | [
{
"begin_idx": "100",
"end_idx": "109",
"entity_id": "D011164",
"entity_type": "Disease",
"text_name": "porphyria"
},
{
"begin_idx": "281",
"end_idx": "313",
"entity_id": "D017119",
"entity_type": "Disease",
"text_name": "familial porphyria cutanea tarda"
},
{
"be... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "26",
"end_idx": "56",
"entity_id": "7389",
"entity_type": "Gene",
"text_name": "uroporphyrinogen decarboxylase"
},
{
"begin_idx": "1570",
"end_idx": "1574",
"entity_id": "7389",
"entity_type": "Gene",
"text_name": "UROD"
}
] | [
{
"begin_idx": "281",
"end_idx": "313",
"entity_id": "D017119",
"entity_type": "Disease",
"text_name": "familial porphyria cutanea tarda"
},
{
"begin_idx": "1786",
"end_idx": "1801",
"entity_id": "D030342",
"entity_type": "Disease",
"text_name": "genetic lesions"
}
] | [
"uroporphyrinogen decarboxylase",
"UROD"
] | [
"familial porphyria cutanea tarda",
"genetic lesions"
] |
8896568 | Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient. | Hirschsprung disease (HSCR), or congenital aganglionic megacolon, is the most common cause of congenital bowel obstruction with an incidence of 1 in 5000 live births. HSCR may be inherited as a single gene disorder with reduced penetrance or as a multigenic trait. HSCR mutations have been identified in the RET receptor tyrosine kinase, endothelin-B receptor (EDNRB) and its physiological ligand, endothelin 3 (EDN3). Although RET's ligand has remained elusive, it is expected to be an extracellular neurotrophic molecule expressed in the developing gut and kidney mesenchyme, based on the phenotypes of intestinal aganglionosis and renal agenesis observed in homozygous RET knockout (Ret -/-) mice. The glial cell line-derived neurotrophic factor (GDNF) is such a molecule. Recently, mice carrying two null alleles for Gdnf were shown to exhibit phenotypes remarkably similar to Ret-/- animals. We screened 106 unrelated HSCR patients for mutations in GDNF by direct sequencing. We identified one familial mutation in a HSCR patient with a known de novo RET mutation and malrotation of the gut. No haplotype sharing was evident in any of 36 HSCR kindreds typed for microsatellite markers surrounding GDNF on human chromosome 5p. Our data suggest that GDNF is a minor contributor to human HSCR susceptibility and that loss of its function in enteric neurogenesis may be compensated for by other neurotrophic factors or via other pathways. However, it may be that in rare instances, RET and GDNF mutations act in concert to produce an enteric phenotype. | [
{
"begin_idx": "86",
"end_idx": "106",
"entity_id": "D006627",
"entity_type": "Disease",
"text_name": "Hirschsprung disease"
},
{
"begin_idx": "116",
"end_idx": "136",
"entity_id": "D006627",
"entity_type": "Disease",
"text_name": "Hirschsprung disease"
},
{
"begi... | [
"Yes",
"Yes",
"Yes",
"Yes",
"No",
"No",
"No",
"No"
] | [
false,
true,
false,
true,
true,
false,
false,
false
] | [
{
"begin_idx": "477",
"end_idx": "482",
"entity_id": "1910",
"entity_type": "Gene",
"text_name": "EDNRB"
},
{
"begin_idx": "428",
"end_idx": "452",
"entity_id": "5979",
"entity_type": "Gene",
"text_name": "receptor tyrosine kinase"
},
{
"begin_idx": "514",
"en... | [
{
"begin_idx": "148",
"end_idx": "180",
"entity_id": "D006627",
"entity_type": "Disease",
"text_name": "congenital aganglionic megacolon"
},
{
"begin_idx": "148",
"end_idx": "180",
"entity_id": "D006627",
"entity_type": "Disease",
"text_name": "congenital aganglionic mega... | [
"EDNRB",
"receptor tyrosine kinase",
"endothelin 3",
"glial cell line-derived neurotrophic factor",
"RET",
"GDNF",
"GDNF",
"glial cell line-derived neurotrophic factor"
] | [
"congenital aganglionic megacolon",
"congenital aganglionic megacolon",
"congenital aganglionic megacolon",
"congenital aganglionic megacolon",
"renal agenesis",
"congenital bowel obstruction",
"congenital bowel obstruction",
"renal agenesis"
] |
8900231 | Expression and molecular analysis of mutations in prolidase deficiency. | Prolidase (E.C.3.4.13.9) cleaves iminodipeptides. Prolidase deficiency (PD; McKusick 170100) is an autosomal recessive disorder with highly variable penetrance. We have identified two novel alleles in the prolidase gene (PEPD) by direct sequencing of PCR-amplified cDNA from a PD individual asymptomatic at age 11 years: a 551G-->A transition in exon 8 (R184Q) and a 833G-->A transition in exon 12 (G278D). To assess the biochemical phenotypes of these and two previously identified PEPD mutations (G448R and delE452), we have designed a transient-expression system for prolidase in COS-1 cells. The enzyme was expressed as a fusion protein carrying an N-terminal tag, the HA1 epitope of influenza hemagglutinin, allowing its immunological discrimination from the endogenous enzyme with a monoclonal antibody. Expression of the R184Q mutation produced 7.4% of control enzymatic activity whereas the expression of the G278D, G448R, and delE452 mutations produced inactive enzymes. Western analysis of the R184Q, G278D, and G448R prolidases revealed stable immunoreactive material whereas the delE452 prolidase was not detectable. Pulse-chase metabolic labeling of cells followed by immunoprecipitation revealed that the delE452 mutant protein was synthesized but had an increased rate of degradation. | [
{
"begin_idx": "760",
"end_idx": "769",
"entity_id": "D007251",
"entity_type": "Disease",
"text_name": "influenza"
},
{
"begin_idx": "171",
"end_idx": "199",
"entity_id": "D030342",
"entity_type": "Disease",
"text_name": "autosomal recessive disorder"
},
{
"begin_... | [
"Yes",
"No"
] | [
true,
false
] | [
{
"begin_idx": "72",
"end_idx": "81",
"entity_id": "5184",
"entity_type": "Gene",
"text_name": "Prolidase"
},
{
"begin_idx": "745",
"end_idx": "748",
"entity_id": "23526",
"entity_type": "Gene",
"text_name": "HA1"
}
] | [
{
"begin_idx": "50",
"end_idx": "70",
"entity_id": "D056732",
"entity_type": "Disease",
"text_name": "prolidase deficiency"
},
{
"begin_idx": "144",
"end_idx": "146",
"entity_id": "D056732",
"entity_type": "Disease",
"text_name": "PD"
}
] | [
"Prolidase",
"HA1"
] | [
"prolidase deficiency",
"PD"
] |
8903321 | The mutation in the mitochondrial aldehyde dehydrogenase (ALDH2) gene responsible for alcohol-induced flushing increases turnover of the enzyme tetramers in a dominant fashion. | Deficiency in mitochondrial aldehyde dehydrogenase (ALDH2), a tetrameric enzyme, results from inheriting one or two ALDH2*2 alleles. This allele encodes a protein subunit with a lysine for glutamate substitution at position 487 and is dominant over the wild-type allele, ALDH2*1. The ALDH2*2-encoded subunit (ALDH2K) reduces the activity of ALDH2 enzyme in cell lines expressing the wild-type subunit (ALDH2E). In addition to this effect on the enzyme activity, we now report that ALDH2*2 heterozygotes had lower levels of ALDH2 immunoreactive protein in autopsy liver samples. The half-lives of ALDH2 protein in HeLa cell lines expressing ALDH2*1, ALDH2*2, or both were determined by the rate of loss of immunoreactive protein after inhibition of protein synthesis with puromycin and by pulse-chase experiments. By either measure, ALDH2E enzyme was very stable, with a half-life of at least 22 h. ALDH2K enzyme had an enzyme half-life of only 14 h. In cells expressing both subunits, most of the subunits assemble as heterotetramers, and these enzymes had a half-life of 13 h. Thus, the effect of ALDH2K on enzyme turnover is dominant. These studies indicate that the ALDH2*2 allele exerts its dominant effect both by interfering with the catalytic activity of the enzyme and by increasing its turnover. This represents the first example of a dominantly acting allele with this effect on a mitochondrial enzyme's turnover. | [
{
"begin_idx": "102",
"end_idx": "129",
"entity_id": "D005483",
"entity_type": "Disease",
"text_name": "flushing increases turnover"
},
{
"begin_idx": "177",
"end_idx": "227",
"entity_id": "D016111",
"entity_type": "Disease",
"text_name": "Deficiency in mitochondrial alde... | [
"Yes",
"No"
] | [
true,
false
] | [
{
"begin_idx": "58",
"end_idx": "63",
"entity_id": "217",
"entity_type": "Gene",
"text_name": "ALDH2"
},
{
"begin_idx": "579",
"end_idx": "584",
"entity_id": "217",
"entity_type": "Gene",
"text_name": "ALDH2"
}
] | [
{
"begin_idx": "102",
"end_idx": "129",
"entity_id": "D005483",
"entity_type": "Disease",
"text_name": "flushing increases turnover"
},
{
"begin_idx": "177",
"end_idx": "227",
"entity_id": "D016111",
"entity_type": "Disease",
"text_name": "Deficiency in mitochondrial alde... | [
"ALDH2",
"ALDH2"
] | [
"flushing increases turnover",
"Deficiency in mitochondrial aldehyde dehydrogenase"
] |
8916969 | Identification of mutations in seven Chinese patients with X-linked chronic granulomatous disease. | X-linked chronic granulomatous disease (CGD) is due to mutations in the gp91phox gene on Xp21.1. Studies in white and Japanese X-linked CGD patients have shown mutations in nearly every exon. We studied the molecular defect of seven Chinese patients with X-linked CGD from six unrelated families. Mutations were located by single-strand conformation polymorphism and then defined by sequence analysis. The mutations were two different amino acid substitutions, a nonsense mutation, an in-frame trinucleotide deletion, a single A insertion causing a frameshift, and a premature stop. Lastly, a rare splice site mutation caused by G to A transition at the terminal nucleotide of exon 3, resulting in the skipping of exon 3, was found. The possible effects of these mutations on protein structure-function or splicing were discussed. Together with previous reports, the A insertion in the run of six As from nucleotide 749 to 754 and the G to A transition at the terminal position of exon 3 may be mutation hotspots of the gp91phox gene. The extreme heterogeneous mutations found in our patients suggest the absence of ethnic group-specific mutation. | [
{
"begin_idx": "59",
"end_idx": "97",
"entity_id": "D006105",
"entity_type": "Disease",
"text_name": "X-linked chronic granulomatous disease"
},
{
"begin_idx": "99",
"end_idx": "137",
"entity_id": "D006105",
"entity_type": "Disease",
"text_name": "X-linked chronic granulo... | [
"Yes"
] | [
true
] | [
{
"begin_idx": "171",
"end_idx": "179",
"entity_id": "1536",
"entity_type": "Gene",
"text_name": "gp91phox"
}
] | [
{
"begin_idx": "59",
"end_idx": "97",
"entity_id": "D006105",
"entity_type": "Disease",
"text_name": "X-linked chronic granulomatous disease"
}
] | [
"gp91phox"
] | [
"X-linked chronic granulomatous disease"
] |
8923886 | Vitamin D receptor gene polymorphisms are associated with osteoporosis in Japanese women. | [
{
"begin_idx": "58",
"end_idx": "70",
"entity_id": "D010024",
"entity_type": "Disease",
"text_name": "osteoporosis"
},
{
"begin_idx": "0",
"end_idx": "18",
"entity_id": "7421",
"entity_type": "Gene",
"text_name": "Vitamin D receptor"
}
] | [
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] | [
true
] | [
{
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"end_idx": "18",
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"entity_type": "Gene",
"text_name": "Vitamin D receptor"
}
] | [
{
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"end_idx": "70",
"entity_id": "D010024",
"entity_type": "Disease",
"text_name": "osteoporosis"
}
] | [
"Vitamin D receptor"
] | [
"osteoporosis"
] | |
8925253 | Schizophrenia and the dopamine-beta-hydroxylase gene: results of a linkage and association study. | Alterations in dopamine neurotransmission and disturbed norepinephrine activity have been implicated in the pathogenesis of schizophrenia. We considered the dopamine-beta-hydroxylase (DBH) gene located on the long arm of chromosome 9 (9q34.3) as a candidate gene for schizophrenia. DBH catalyzes the synthesis of norepinephrine from dopamine in noradrenergic neurons. In addition to DBH we used in the linkage study DNA markers ABL (centromeric) and D9S114 (telomeric). The aim of this study was to test linkage and association between PCR-based genotyped markers and schizophrenia. A simulation was done to investigate the power of our sample. In 34 Austrian families we could not detect linkage between schizophrenia and schizophrenia spectrum disorders and the three genetic markers. We could not find any significant deviation in allelic or genotypic distribution from expectations. Based on our results we conclude that the DBH gene seems to have no strong contribution in the etiology of schizophrenia. | [
{
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"end_idx": "13",
"entity_id": "D012559",
"entity_type": "Disease",
"text_name": "Schizophrenia"
},
{
"begin_idx": "222",
"end_idx": "235",
"entity_id": "D012559",
"entity_type": "Disease",
"text_name": "schizophrenia"
},
{
"begin_idx": "365",
... | [
"Yes"
] | [
true
] | [
{
"begin_idx": "22",
"end_idx": "47",
"entity_id": "1621",
"entity_type": "Gene",
"text_name": "dopamine-beta-hydroxylase"
}
] | [
{
"begin_idx": "0",
"end_idx": "13",
"entity_id": "D012559",
"entity_type": "Disease",
"text_name": "Schizophrenia"
}
] | [
"dopamine-beta-hydroxylase"
] | [
"Schizophrenia"
] |
8931914 | An insertion/deletion polymorphism in the angiotensin converting enzyme gene is associated with both brain substance P contents and affective disorders. | Because of a potent action of angiotensin converting enzyme (ACE) to degrade substance P (SP) and an association of the insertion/deletion (I/D) polymorphism of the ACE gene with ACE activity, an association between the SP level and the ACE I/D polymorphism were examined using 20 human postmortem brain samples. The results showed a significant association between the polymorphism and SP levels in the basal ganglia and substantia nigra, where both ACE and SP concentrate, and a higher SP level in the subjects with the DD genotype than in those with the II genotype, with an intermediate level in heterozygotes. Associations of the polymorphism with schizophrenia and affective disorders were also investigated in 292 unrelated Japanese schizophrenics, 65 patients with affective disorders, and 579 controls. The D allele was significantly more frequent in the patients with affective disorders than in the controls (p < .02), and the DD genotype was significantly more frequent in the patients with affective disorders than in the controls (p < .002). There is no significant difference in the frequencies of the allele and the genotype between the controls and schizophrenics. These results suggest that the ACE I/D polymorphism is one of the genetic factors for an interindividual variability of brain SP levels, and that the ACE polymorphism may contribute to the susceptibility to affective disorders. | [
{
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"end_idx": "677",
"entity_id": "C536170",
"entity_type": "Disease",
"text_name": "DD"
},
{
"begin_idx": "1091",
"end_idx": "1093",
"entity_id": "C536170",
"entity_type": "Disease",
"text_name": "DD"
},
{
"begin_idx": "806",
"end_idx": "81... | [
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"No"
] | [
true,
true
] | [
{
"begin_idx": "42",
"end_idx": "71",
"entity_id": "1636",
"entity_type": "Gene",
"text_name": "angiotensin converting enzyme"
},
{
"begin_idx": "641",
"end_idx": "643",
"entity_id": "6863",
"entity_type": "Gene",
"text_name": "SP"
}
] | [
{
"begin_idx": "132",
"end_idx": "151",
"entity_id": "D019964",
"entity_type": "Disease",
"text_name": "affective disorders"
},
{
"begin_idx": "675",
"end_idx": "677",
"entity_id": "C536170",
"entity_type": "Disease",
"text_name": "DD"
}
] | [
"angiotensin converting enzyme",
"SP"
] | [
"affective disorders",
"DD"
] |
8937196 | [Growth hormone prevents the steroid myopathy in rats]. | To clarify whether growth hormone possesses the counteracting effect on steroid myopathy, we examined the influence of simultaneous administration of recombinant human growth hormone (rhGH) with glucocorticoid on the diameter of muscle fibers in rats. Female Sprague-Dawley rats weighing 120-140 g were divided into four groups. A group treated with glucocorticoid alone was subcutaneously injected with 5 mg/kg/day triamcinolone, a GH-treated group with 10 IU/kg/day rhGH alone, a steroid-GH-group with the same doses of glucocorticoid and rhGH. The control rats were injected with the vehicle alone. After 14 days of treatment, each rat was anesthetized with ether and subjected to muscle biopsy of extensor digitorum longus (EDL) and soleus. Administration of rhGH alone failed to affect the diameter of muscle fibers in either EDL or soleus. Glucocorticoid treatment caused a significant reduction in the diameter of muscle fibers in the EDL, compared with the control. In the type II muscle fibers of the EDL, simultaneous administration of rhGH attenuated glucocorticoid-induced muscle atrophy significantly. We concluded that GH administration would at least partially prevents steroid myopathy. | [
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"end_idx": "1155",
"entity_id": "D009133",
"entity_type": "Disease",
"text_name": "muscle atrophy"
},
{
"begin_idx": "29",
"end_idx": "45",
"entity_id": "D009135",
"entity_type": "Disease",
"text_name": "steroid myopathy"
},
{
"begin_idx": "... | [
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"No"
] | [
false,
true
] | [
{
"begin_idx": "75",
"end_idx": "89",
"entity_id": "2688",
"entity_type": "Gene",
"text_name": "growth hormone"
},
{
"begin_idx": "75",
"end_idx": "89",
"entity_id": "2688",
"entity_type": "Gene",
"text_name": "growth hormone"
}
] | [
{
"begin_idx": "1141",
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"entity_id": "D009133",
"entity_type": "Disease",
"text_name": "muscle atrophy"
},
{
"begin_idx": "29",
"end_idx": "45",
"entity_id": "D009135",
"entity_type": "Disease",
"text_name": "steroid myopathy"
}
] | [
"growth hormone",
"growth hormone"
] | [
"muscle atrophy",
"steroid myopathy"
] |
8956044 | Three new mutations (P183T, V150L, 528insG) and eleven sequence polymorphisms in Italian patients with galactose-1-phosphate uridyltransferase (GALT) deficiency. | [
{
"begin_idx": "103",
"end_idx": "160",
"entity_id": "D005693",
"entity_type": "Disease",
"text_name": "galactose-1-phosphate uridyltransferase (GALT) deficiency"
},
{
"begin_idx": "144",
"end_idx": "148",
"entity_id": "2592",
"entity_type": "Gene",
"text_name": "GALT"
... | [
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true
] | [
{
"begin_idx": "144",
"end_idx": "148",
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"entity_type": "Gene",
"text_name": "GALT"
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] | [
{
"begin_idx": "103",
"end_idx": "160",
"entity_id": "D005693",
"entity_type": "Disease",
"text_name": "galactose-1-phosphate uridyltransferase (GALT) deficiency"
}
] | [
"GALT"
] | [
"galactose-1-phosphate uridyltransferase (GALT) deficiency"
] | |
8964908 | Plasma increase of interleukin-12 and interferon-gamma. Pathological significance in autism. | Immune factors such as autoimmunity have been implicated in the genesis of autism, a neurodevelopmental disorder. Since autoimmune response involves immune activation, the plasma levels of interferon-alpha (IFN-alpha), interferon-gamma (IFN-gamma), interleukin-12 (IL-12), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and soluble intercellular adhesion molecule-1 (sICAM-1) were measured in autistic patients and age-matched normal controls. The levels of IL-12 and IFN-gamma were significantly (P < or = 0.05) higher in patients as compared to controls. However, IFN-alpha, IL-6, TNF-alpha, and sICAM-1 levels did not significantly differ between the two groups. Because macrophage-derived IL-12 is known to selectively induce IFN-gamma in T helper type-1 (Th-1) cells, it is suggested that IL-12 and IFN-gamma increases may indicate antigenic stimulation of Th-1 cells pathogenetically linked to autoimmunity in autism. | [
{
"begin_idx": "85",
"end_idx": "91",
"entity_id": "D001321",
"entity_type": "Disease",
"text_name": "autism"
},
{
"begin_idx": "168",
"end_idx": "174",
"entity_id": "D001321",
"entity_type": "Disease",
"text_name": "autism"
},
{
"begin_idx": "502",
"end_idx":... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "366",
"end_idx": "379",
"entity_id": "3569",
"entity_type": "Gene",
"text_name": "interleukin-6"
},
{
"begin_idx": "675",
"end_idx": "684",
"entity_id": "3439",
"entity_type": "Gene",
"text_name": "IFN-alpha"
}
] | [
{
"begin_idx": "502",
"end_idx": "510",
"entity_id": "D001321",
"entity_type": "Disease",
"text_name": "autistic"
},
{
"begin_idx": "502",
"end_idx": "510",
"entity_id": "D001321",
"entity_type": "Disease",
"text_name": "autistic"
}
] | [
"interleukin-6",
"IFN-alpha"
] | [
"autistic",
"autistic"
] |
8988970 | Association analysis of the catechol O-methyltransferase gene and bipolar affective disorder. | OBJECTIVE: Catechol O-methyltransferase (COMT) is an enzyme that inactivates catecholamines. Two common COMT alleles determine high and low activity of the enzyme. Previous studies using biochemical methods found lower enzyme activity in patients with major depression and bipolar disorder in comparison with control values, suggesting that a dysfunction in catecholamine metabolism may be related to the etiology of depression. METHOD: The authors studied two recently described DNA polymorphisms at the COMT gene (a silent C256G mutation and a structural mutation, Val-108-Met) in 88 patients with bipolar disorder and in 113 healthy comparison subjects, all of Spanish origin. RESULTS: The frequency of the C256 allele was 0.58 in the patients and 0.54 in the comparison subjects. The frequency of the Val108 variant was 0.57 for both the patients and the comparison subjects. No allelic or genotypic associations were observed. CONCLUSIONS: The lack of association suggests that the COMT gene is not a major risk factor for bipolar disorder. | [
{
"begin_idx": "66",
"end_idx": "92",
"entity_id": "D001714",
"entity_type": "Disease",
"text_name": "bipolar affective disorder"
},
{
"begin_idx": "367",
"end_idx": "383",
"entity_id": "D001714",
"entity_type": "Disease",
"text_name": "bipolar disorder"
},
{
"beg... | [
"Yes",
"No"
] | [
true,
false
] | [
{
"begin_idx": "28",
"end_idx": "56",
"entity_id": "1312",
"entity_type": "Gene",
"text_name": "catechol O-methyltransferase"
},
{
"begin_idx": "135",
"end_idx": "139",
"entity_id": "1312",
"entity_type": "Gene",
"text_name": "COMT"
}
] | [
{
"begin_idx": "66",
"end_idx": "92",
"entity_id": "D001714",
"entity_type": "Disease",
"text_name": "bipolar affective disorder"
},
{
"begin_idx": "346",
"end_idx": "362",
"entity_id": "D003866",
"entity_type": "Disease",
"text_name": "major depression"
}
] | [
"catechol O-methyltransferase",
"COMT"
] | [
"bipolar affective disorder",
"major depression"
] |
8989248 | CTLA4 alanine-17 confers genetic susceptibility to Graves' disease and to type 1 diabetes mellitus. | The genetic susceptibility to Graves' disease and type 1 (insulin-dependent) diabetes mellitus is conferred by genes in the human leukocyte antigen region on the short arm of chromosome 6, but several other genes are presumed to determine disease susceptibility. Among those candidate genes is the cytotoxic T lymphocyte antigen 4 (CTLA4) located on chromosome 2q33 in man. We investigated the distribution of the CTLA4 exon 1 polymorphism (49 A/G) in Graves' disease and IDDM. This dimorphism at codon 17 results in an amino acid exchange (Thr/Ala) in the leader peptide of the expressed protein and was analyzed by PCR, single strand conformation polymorphism, and restriction fragment length polymorphism analysis in 305 patients with Graves' disease, 293 patients with IDDM, and 325 controls. Patients with Graves' disease had significantly more Ala alleles than controls, both as homozygotes (21% vs. 13%) and as heterozygotes (53% vs. 46%), and less Thr as homozygotes (26% vs. 42%; P < 2 x 10(-4). The phenotypic frequency of Ala-positive patients (73%) was significantly higher than of controls (58%; P = 10(-4); relative risk = 2). Patients with IDDM also had significantly more Ala alleles as homozygotes (19%) or heterozygotes (50%; P = 0.01). In conclusion, an alanine at codon 17 of CTLA4 is associated with genetic susceptibility to Graves' disease as well as to IDDM. | [
{
"begin_idx": "51",
"end_idx": "98",
"entity_id": "D003920",
"entity_type": "Disease",
"text_name": "Graves' disease and to type 1 diabetes mellitus"
},
{
"begin_idx": "130",
"end_idx": "194",
"entity_id": "D003922",
"entity_type": "Disease",
"text_name": "Graves' diseas... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "398",
"end_idx": "430",
"entity_id": "1493",
"entity_type": "Gene",
"text_name": "cytotoxic T lymphocyte antigen 4"
},
{
"begin_idx": "432",
"end_idx": "437",
"entity_id": "1493",
"entity_type": "Gene",
"text_name": "CTLA4"
}
] | [
{
"begin_idx": "130",
"end_idx": "194",
"entity_id": "D003922",
"entity_type": "Disease",
"text_name": "Graves' disease and type 1 (insulin-dependent) diabetes mellitus"
},
{
"begin_idx": "911",
"end_idx": "926",
"entity_id": "D006111",
"entity_type": "Disease",
"text_nam... | [
"cytotoxic T lymphocyte antigen 4",
"CTLA4"
] | [
"Graves' disease and type 1 (insulin-dependent) diabetes mellitus",
"Graves' disease"
] |
8990002 | Molecular analysis of the APC gene in 105 Dutch kindreds with familial adenomatous polyposis: 67 germline mutations identified by DGGE, PTT, and southern analysis. | Germline mutations of the adenomatous polyposis coli (APC) gene are responsible for familial adenomatous polyposis (FAP), an autosomal dominant predisposition to colorectal cancer. We screened the entire coding region of the APC gene for mutations in an unselected series of 105 Dutch FAP kindreds. For the analysis of exons 1-14, we employed the GC-clamped denaturing gradient gel electrophoresis (DGGE), while the large exon 15 was examined using the protein truncation test. Using this approach, we identified 65 pathogenic mutations in the above 105 apparently unrelated FAP families. The mutations were predominantly either frameshifts (39/65) or single base substitutions (18/65), resulting in premature stop codons. Mutations that would predict abnormal RNA splicing were identified in seven cases. In one of the families, a nonconservative amino acid change was found to segregate with the disease. In spite of the large number of APC mutations reported to date, we identified 27 novel germline mutations in our patients, which reiterates the great heterogeneity of the mutation spectrum in FAP. In addition to the point mutations identified in our patients, structural rearrangements of APC were found in two pedigrees, by Southern blot analysis. The present study indicates that the combined use of DGGE, protein truncation test, and Southern blot analysis offers an efficient strategy for the presymptomatic diagnosis of FAP by direct mutation detection. We found that the combined use of the currently available molecular approaches still fails to identify the underlying genetic defect in a significant subset of the FAP families. The possible causes for this limitation are discussed. | [
{
"begin_idx": "26",
"end_idx": "29",
"entity_id": "D011125",
"entity_type": "Disease",
"text_name": "APC"
},
{
"begin_idx": "62",
"end_idx": "92",
"entity_id": "D011125",
"entity_type": "Disease",
"text_name": "familial adenomatous polyposis"
},
{
"begin_idx": "1... | [
"Yes",
"No"
] | [
true,
false
] | [
{
"begin_idx": "26",
"end_idx": "29",
"entity_id": "324",
"entity_type": "Gene",
"text_name": "APC"
},
{
"begin_idx": "389",
"end_idx": "392",
"entity_id": "324",
"entity_type": "Gene",
"text_name": "APC"
}
] | [
{
"begin_idx": "62",
"end_idx": "92",
"entity_id": "D011125",
"entity_type": "Disease",
"text_name": "familial adenomatous polyposis"
},
{
"begin_idx": "1748",
"end_idx": "1762",
"entity_id": "D030342",
"entity_type": "Disease",
"text_name": "genetic defect"
}
] | [
"APC",
"APC"
] | [
"familial adenomatous polyposis",
"genetic defect"
] |
9000709 | No independent associations of LMP2 and LMP7 polymorphisms with susceptibility to develop IDDM. | Results from a recent study suggested that polymorphisms within the HLA class II genes LMP2 and LMP7 were associated with the susceptibility for developing IDDM, and that this association could not be explained by linkage disequilibrium to HLA-DR or -DQ genes. We typed 285 IDDM patients and 337 HLA-DRB1-DQA1-DQB1 genotypically matched control subjects from an ethnically homogeneous population for both the G/T polymorphism in intron 6 of the LMP7 gene and the Arg-His polymorphism in the LMP2 gene. In addition, we typed IDDM families in which at least one parent was homozygous for a DRB1-DQA1-DQB1 haplotype and performed a transmission/disequilibrium test of these LMP polymorphisms. Our data suggest that none of these LMP2 or LMP7 polymorphisms are independently associated with IDDM susceptibility, in contrast to what has been previously reported by others. Further, our results suggest that one partial explanation for the previously reported independent association between IDDM and these LMP polymorphisms may have been that patients and control subjects were not matched for DRB1*04 subtypes. Our results emphasize the need for a complete matching for DRB1, DQA1, and DQB1 alleles between patients and control subjects when attempting to detect independent effects of other polymorphisms in the HLA complex on IDDM susceptibility or protection. | [
{
"begin_idx": "90",
"end_idx": "94",
"entity_id": "D003922",
"entity_type": "Disease",
"text_name": "IDDM"
},
{
"begin_idx": "252",
"end_idx": "256",
"entity_id": "D003922",
"entity_type": "Disease",
"text_name": "IDDM"
},
{
"begin_idx": "370",
"end_idx": "37... | [
"Yes",
"Yes",
"No",
"No"
] | [
true,
true,
true,
true
] | [
{
"begin_idx": "40",
"end_idx": "44",
"entity_id": "5696",
"entity_type": "Gene",
"text_name": "LMP7"
},
{
"begin_idx": "31",
"end_idx": "35",
"entity_id": "5698",
"entity_type": "Gene",
"text_name": "LMP2"
},
{
"begin_idx": "1262",
"end_idx": "1266",
"ent... | [
{
"begin_idx": "90",
"end_idx": "94",
"entity_id": "D003922",
"entity_type": "Disease",
"text_name": "IDDM"
},
{
"begin_idx": "90",
"end_idx": "94",
"entity_id": "D003922",
"entity_type": "Disease",
"text_name": "IDDM"
},
{
"begin_idx": "1420",
"end_idx": "142... | [
"LMP7",
"LMP2",
"DRB1",
"DQA1"
] | [
"IDDM",
"IDDM",
"IDDM",
"IDDM"
] |
9003501 | Mutational and functional analysis of the neurofibromatosis type 1 (NF1) gene. | Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders. It is caused by mutations in the NF1 gene which comprises 60 exons and is located on chromosome 17q. The NF1 gene product, neurofibromin, displays partial homology to GTPase-activating protein (GAP). The GAP-related domain (GRD), encoded by exons 20-27a, is the only region of neurofibromin to which a biological function has been ascribed. A total of 320 unrelated NF1 patients were screened for mutations in the GRD-encoding region of the NF1 gene. Sixteen different lesions in the NF1 GRD region were identified in a total of 20 patients. Of these lesions, 14 are novel and together comprise three missense, two nonsense and three splice site mutations plus six deletions of between 1 and 4 bp. The effect of one of the missense mutations (R1391S) was studied by in vitro expression of a site-directed mutant and GAP activity assay. The mutant protein, R1391S, was found to be some 300-fold less active than wild-type NF1 GRD. The mutations reported in this study therefore provide further material for the functional analysis of neurofibromin as well as an insight into the mutational spectrum of the NF1 GRD. | [
{
"begin_idx": "370",
"end_idx": "388",
"entity_id": "C567341",
"entity_type": "Disease",
"text_name": "GAP-related domain"
},
{
"begin_idx": "390",
"end_idx": "393",
"entity_id": "C567341",
"entity_type": "Disease",
"text_name": "GRD"
},
{
"begin_idx": "654",
... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "42",
"end_idx": "66",
"entity_id": "4763",
"entity_type": "Gene",
"text_name": "neurofibromatosis type 1"
},
{
"begin_idx": "607",
"end_idx": "610",
"entity_id": "4763",
"entity_type": "Gene",
"text_name": "NF1"
}
] | [
{
"begin_idx": "42",
"end_idx": "66",
"entity_id": "D009456",
"entity_type": "Disease",
"text_name": "neurofibromatosis type 1"
},
{
"begin_idx": "390",
"end_idx": "393",
"entity_id": "C567341",
"entity_type": "Disease",
"text_name": "GRD"
}
] | [
"neurofibromatosis type 1",
"NF1"
] | [
"neurofibromatosis type 1",
"GRD"
] |
9007616 | A novel missense mutation (Asn5-->Ile) in lecithin: cholesterol acyltransferase (LCAT) gene in a Japanese patient with LCAT deficiency. | We identified a novel missense mutation in the lecithin:cholesterol acyltransferase gene in a new case of lecithin:cholesterol acyltransferase (LCAT) deficiency. The patient was a 64-year-old diabetic Japanese male who showed an extremely low level of serum high-density lipoprotein-cholesterol, corneal opacities, anemia, and proteinuria. Both the patient's LCAT activity and mass were markedly low. DNA sequence analysis of the LCAT gene showed an A-to-T transition at base 97 in exon 1, and predicted a change in asparagine to isoleucine at the 5th amino acid of the protein. Restriction analysis of polymerase chain reaction-amplified DNA using Ase I showed that the patient was homozygous for this mutation. Our results suggested that asparagine 5 was an important amino acid and substitution with isoleucine caused marked reduction of LCAT activity and mass, resulting in LCAT deficiency. | [
{
"begin_idx": "451",
"end_idx": "457",
"entity_id": "D000740",
"entity_type": "Disease",
"text_name": "anemia"
},
{
"begin_idx": "440",
"end_idx": "449",
"entity_id": "D002386",
"entity_type": "Disease",
"text_name": "opacities"
},
{
"begin_idx": "119",
"end_... | [
"Yes",
"No"
] | [
true,
false
] | [
{
"begin_idx": "42",
"end_idx": "79",
"entity_id": "3931",
"entity_type": "Gene",
"text_name": "lecithin: cholesterol acyltransferase"
},
{
"begin_idx": "566",
"end_idx": "570",
"entity_id": "3931",
"entity_type": "Gene",
"text_name": "LCAT"
}
] | [
{
"begin_idx": "251",
"end_idx": "296",
"entity_id": "D007863",
"entity_type": "Disease",
"text_name": "cholesterol acyltransferase (LCAT) deficiency"
},
{
"begin_idx": "451",
"end_idx": "457",
"entity_id": "D000740",
"entity_type": "Disease",
"text_name": "anemia"
}
] | [
"lecithin: cholesterol acyltransferase",
"LCAT"
] | [
"cholesterol acyltransferase (LCAT) deficiency",
"anemia"
] |
9012407 | Identification of mutations in cystatin B, the gene responsible for the Unverricht-Lundborg type of progressive myoclonus epilepsy (EPM1). | Progressive myoclonus epilepsy (EPM1) is an autosomal recessive disorder, characterized by severe, stimulus-sensitive myoclonus and tonic-clonic seizures. The EPM1 locus was mapped to within 0.3 cM from PFKL in chromosome 21q22.3. The gene for the proteinase inhibitor cystatin B was recently localized in the EPM1 critical region, and mutations were identified in two EPM1 families. We have identified six nucleotide changes in the cystatin B gene of non-Finnish EPM1 families from northern Africa and Europe. The 426G-->C change in exon 1 results in a Gly4Arg substitution and is the first missense mutation described that is associated with EPM1. Molecular modeling predicts that this substitution severely affects the contact of cystatin B with papain. Mutations in the invariant AG dinucleotides of the acceptor sites of introns 1 and 2 probably result in abnormal splicing. A deletion of two nucleotides in exon 3 produces a frameshift and truncates the protein. Therefore, these four mutations are all predicted to impair the production of functional protein. These mutations were found in 7 of the 29 unrelated EPM1 patients analyzed, in homozygosity in 1, and in heterozygosity in the others. The remaining two sequence changes, 431G-->T and 2575A-->G, probably represent polymorphic variants. In addition, a tandem repeat in the 5' UTR (CCCCGCCCCGCG) is present two or three times in normal alleles. It is peculiar that in the majority of patients no mutations exist within the exons and splice sites of the cystatin B gene. | [
{
"begin_idx": "112",
"end_idx": "130",
"entity_id": "D004831",
"entity_type": "Disease",
"text_name": "myoclonus epilepsy"
},
{
"begin_idx": "151",
"end_idx": "169",
"entity_id": "D004831",
"entity_type": "Disease",
"text_name": "myoclonus epilepsy"
},
{
"begin_i... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "31",
"end_idx": "41",
"entity_id": "1476",
"entity_type": "Gene",
"text_name": "cystatin B"
},
{
"begin_idx": "449",
"end_idx": "453",
"entity_id": "1476",
"entity_type": "Gene",
"text_name": "EPM1"
}
] | [
{
"begin_idx": "132",
"end_idx": "136",
"entity_id": "D020194",
"entity_type": "Disease",
"text_name": "EPM1"
},
{
"begin_idx": "257",
"end_idx": "266",
"entity_id": "D009207",
"entity_type": "Disease",
"text_name": "myoclonus"
}
] | [
"cystatin B",
"EPM1"
] | [
"EPM1",
"myoclonus"
] |
9020854 | Retinopathy induced in mice by targeted disruption of the rhodopsin gene. | Retinitis pigmentosa (RP) represents the most common mendelian degenerative retinopathy of man, involving death of rod photoreceptors, cone cell degeneration, retinal vessel attenuation and pigmentary deposits. The patient experiences night blindness, usually followed by progressive loss of visual field. Genetic linkage between an autosomal dominant RP locus and rhodopsin, the photoreactive pigment of the rod cells, led to the identification of mutations within the rhodopsin gene in both dominant and recessive forms of RP. To better understand the functional and structural role of rhodopsin in the normal retina and in the pathogenesis of retinal disease, we generated mice carrying a targeted disruption of the rhodopsin gene. Rho-/- mice do not elaborate rod outer segments, losing their photoreceptors over 3 months. There is no rod ERG response in 8-week-old animals. Rho+/- animals retain the majority of their photoreceptors although the inner and outer segments of these cells display some structural disorganization, the outer segments becoming shorter in older mice. These animals should provide a useful genetic background on which to express other mutant opsin transgenes, as well as a model to assess the therapeutic potential of re-introducing functional rhodopsin genes into degenerating retinal tissues. | [
{
"begin_idx": "209",
"end_idx": "259",
"entity_id": "C566719",
"entity_type": "Disease",
"text_name": "cone cell degeneration, retinal vessel attenuation"
},
{
"begin_idx": "309",
"end_idx": "324",
"entity_id": "D009755",
"entity_type": "Disease",
"text_name": "night bli... | [
"Yes",
"No"
] | [
true,
false
] | [
{
"begin_idx": "58",
"end_idx": "67",
"entity_id": "6010",
"entity_type": "Gene",
"text_name": "rhodopsin"
},
{
"begin_idx": "544",
"end_idx": "553",
"entity_id": "6010",
"entity_type": "Gene",
"text_name": "rhodopsin"
}
] | [
{
"begin_idx": "74",
"end_idx": "94",
"entity_id": "D012174",
"entity_type": "Disease",
"text_name": "Retinitis pigmentosa"
},
{
"begin_idx": "264",
"end_idx": "283",
"entity_id": "D058225",
"entity_type": "Disease",
"text_name": "pigmentary deposits"
}
] | [
"rhodopsin",
"rhodopsin"
] | [
"Retinitis pigmentosa",
"pigmentary deposits"
] |
9036918 | Mutations in the COL3A1 gene result in the Ehlers-Danlos syndrome type IV and alterations in the size and distribution of the major collagen fibrils of the dermis. | Ehlers-Danlos syndrome type IV (EDS type IV) results from heterozygosity for mutations in the COL3A1 gene that encodes the chains of type III procollagen. By using light, transmission, and scanning electron microscopy, we examined skin biopsies from 22 individuals with EDS type IV in whom the COL3A1 mutations had been identified. The most striking changes in EDS type IV were correlated with point mutations that substituted a residue for a glycine near the carboxyl-terminal end of the triple-helical domain of pro alpha1(III). In three cases with the mutation G1012R, G1018V, or G1021E, cells in the dermis had extremely dilated rough endoplasmic reticulum (RER), the dermis was thin, and there was a reduced proportion of collagen although the proportion of elastic fibers appeared increased. In these tissues, collagen fibrils were small (65-80 nm) compared to normal (95-110 nm). Fibrils 80-90 nm in diameter and moderately dilated RER were found with mutations G769R, G373R, and G061E and with exon-skipping mutations of exons 34 and 45. With mutations G034R and G016C and exon-skipping mutations that deleted the sequences of exons 7, 8, 14, 18, 24, and 27, fibrils were more variable in size (85-120 nm). The composite collagen fibrils characteristic of EDS types I and II were not found in EDS type IV. These findings indicate that mutations in the COL3A1 gene have effects on secretion, fibrillogenesis, and skin architecture that reflect the position and nature of the mutation. | [
{
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"end_idx": "73",
"entity_id": "D004535",
"entity_type": "Disease",
"text_name": "Ehlers-Danlos syndrome type IV"
},
{
"begin_idx": "164",
"end_idx": "194",
"entity_id": "D004535",
"entity_type": "Disease",
"text_name": "Ehlers-Danlos syndrome type IV"... | [
"Yes",
"No"
] | [
true,
false
] | [
{
"begin_idx": "17",
"end_idx": "23",
"entity_id": "1281",
"entity_type": "Gene",
"text_name": "COL3A1"
},
{
"begin_idx": "258",
"end_idx": "264",
"entity_id": "1281",
"entity_type": "Gene",
"text_name": "COL3A1"
}
] | [
{
"begin_idx": "43",
"end_idx": "73",
"entity_id": "D004535",
"entity_type": "Disease",
"text_name": "Ehlers-Danlos syndrome type IV"
},
{
"begin_idx": "1103",
"end_idx": "1106",
"entity_id": "D008228",
"entity_type": "Disease",
"text_name": "RER"
}
] | [
"COL3A1",
"COL3A1"
] | [
"Ehlers-Danlos syndrome type IV",
"RER"
] |
9042913 | Mutations in the COL5A1 gene are causal in the Ehlers-Danlos syndromes I and II. | The Ehlers-Danlos syndrome (EDS) is a heterogeneous connective-tissue disorder of which at least nine subtypes are recognized. Considerable clinical overlap exists between the EDS I and II subtypes, suggesting that both are allelic disorders. Recent evidence based on linkage and transgenic mice studies suggest that collagen V is causally involved in human EDS. Collagen V forms heterotypic fibrils with collagen I in many tissues and plays an important role in collagen I fibrillogenesis. We have identified a mutation in COL5A1, the gene encoding the pro(alpha)1(V) collagen chain, segregating with EDS I in a four-generation family. The mutation causes the substitution of the most 5' cysteine residue by a serine within a highly conserved sequence of the pro(alpha)1(V) C-propeptide domain and causes reduction of collagen V by preventing incorporation of the mutant pro(alpha)1(V) chains in the collagen V trimers. In addition, we have detected splicing defects in the COL5A1 gene in a patient with EDS I and in a family with EDS II. These findings confirm the causal role of collagen V in at least a subgroup of EDS I, prove that EDS I and II are allelic conditions, and represent a, so far, unique example of a human collagen disorder caused by substitution of a highly conserved cysteine residue in the C-propeptide domain of a fibrillar collagen. | [
{
"begin_idx": "47",
"end_idx": "72",
"entity_id": "C536194",
"entity_type": "Disease",
"text_name": "Ehlers-Danlos syndromes I"
},
{
"begin_idx": "257",
"end_idx": "262",
"entity_id": "C536194",
"entity_type": "Disease",
"text_name": "EDS I"
},
{
"begin_idx": "68... | [
"Yes",
"No"
] | [
true,
false
] | [
{
"begin_idx": "635",
"end_idx": "649",
"entity_id": "1289",
"entity_type": "Gene",
"text_name": "pro(alpha)1(V)"
},
{
"begin_idx": "841",
"end_idx": "855",
"entity_id": "1289",
"entity_type": "Gene",
"text_name": "pro(alpha)1(V)"
}
] | [
{
"begin_idx": "1113",
"end_idx": "1119",
"entity_id": "C536195",
"entity_type": "Disease",
"text_name": "EDS II"
},
{
"begin_idx": "1306",
"end_idx": "1323",
"entity_id": "D003095",
"entity_type": "Disease",
"text_name": "collagen disorder"
}
] | [
"pro(alpha)1(V)",
"pro(alpha)1(V)"
] | [
"EDS II",
"collagen disorder"
] |
9058314 | Analysis of an interferon-gamma gene (IFNG) polymorphism in Danish and Finnish insulin-dependent diabetes mellitus (IDDM) patients and control subjects. Danish Study Group of Diabetes in Childhood. | A CA-repeat polymorphism within the first intron of the interferon (IFN)-gamma gene was analyzed. This polymorphism was recently demonstrated to be associated with insulin-dependent diabetes mellitus (IDDM) in Japanese subjects. We typed 266 IDDM patients and 195 control subjects of Danish Caucasoid origin. No significant differences in allele or genotype frequencies between patients and control were observed. In addition, we typed 168 IDDM and 110 control subjects of Finnish origin. A significant disease association of the studied IFN-gamma allelic pattern was found (p = 0.029). Analysis of data according to HLA-DQB1 susceptibility status did not reveal heterogeneity of risk at the IFN-gamma locus in either of the populations. Fifty-five Danish and 94 Finnish IDDM multiplex families with at least two affected siblings (660 individuals) were typed to test for transmission disequilibrium (TDT). No evidence for overall transmission disequilibrium using either an allele-wise (p = 0.42; combined data) or a genotype-wise analysis (p = 0.21; combined data) could be detected. Thus, the modest significance level observed in the Finnish case-control study and the failure to replicate it by the TDT provide little support for the hypothesis that the IFN-gamma gene microsatellite is associated with IDDM. | [
{
"begin_idx": "175",
"end_idx": "183",
"entity_id": "D003920",
"entity_type": "Disease",
"text_name": "Diabetes"
},
{
"begin_idx": "79",
"end_idx": "114",
"entity_id": "D003922",
"entity_type": "Disease",
"text_name": "insulin-dependent diabetes mellitus"
},
{
"b... | [
"Yes",
"No"
] | [
true,
false
] | [
{
"begin_idx": "254",
"end_idx": "276",
"entity_id": "3458",
"entity_type": "Gene",
"text_name": "interferon (IFN)-gamma"
},
{
"begin_idx": "815",
"end_idx": "823",
"entity_id": "3119",
"entity_type": "Gene",
"text_name": "HLA-DQB1"
}
] | [
{
"begin_idx": "79",
"end_idx": "114",
"entity_id": "D003922",
"entity_type": "Disease",
"text_name": "insulin-dependent diabetes mellitus"
},
{
"begin_idx": "79",
"end_idx": "114",
"entity_id": "D003922",
"entity_type": "Disease",
"text_name": "insulin-dependent diabetes... | [
"interferon (IFN)-gamma",
"HLA-DQB1"
] | [
"insulin-dependent diabetes mellitus",
"insulin-dependent diabetes mellitus"
] |
9065719 | Immunohistochemical detection of p53 protein in rhabdomyosarcoma: association with clinicopathological features and outcome. | PURPOSE: Alteration in the p53 tumor suppressor gene is the most common tumor specific genetic change identified in most major cancer types including rhabdomyosarcomas. To investigate the overexpression of p53 and its relation to clinical features and outcome in patients with rhabdomyosarcoma (RMS), an immunocytochemical study was performed. METHODS: Formalin-fixed paraffin embedded tissue sections obtained from 42 cases of RMS were immunostained with a mouse monoclonal antibody p53-D07. Staining was assessed by evaluating the percentage of p53 immunopositive cancer cell nuclei. RESULTS: Nuclear accumulation of p53 protein was detected in 8 of 42 (19%) samples. Clinical analyses of patients demonstrated no correlation between positive staining and age, sex, histological subtype, stage and overall survival. This analysis, however, was limited by the small number of patients who demonstrated p53 immunostaining. Nonetheless, a statistically significant association was observed between p53 expression and adverse outcome. Nuclear p53 expression was associated with disease progression or recurrence (p <0.001) and with a worse event free survival (p = 0.0015). CONCLUSION: The nuclear p53 immunoreaction rate is low in RMS, but p53 expression appears to correlate with poor prognosis. | [
{
"begin_idx": "156",
"end_idx": "161",
"entity_id": "D009369",
"entity_type": "Disease",
"text_name": "tumor"
},
{
"begin_idx": "197",
"end_idx": "202",
"entity_id": "D009369",
"entity_type": "Disease",
"text_name": "tumor"
},
{
"begin_idx": "252",
"end_idx":... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "33",
"end_idx": "36",
"entity_id": "7157",
"entity_type": "Gene",
"text_name": "p53"
},
{
"begin_idx": "331",
"end_idx": "334",
"entity_id": "7157",
"entity_type": "Gene",
"text_name": "p53"
}
] | [
{
"begin_idx": "275",
"end_idx": "292",
"entity_id": "D012208",
"entity_type": "Disease",
"text_name": "rhabdomyosarcomas"
},
{
"begin_idx": "212",
"end_idx": "226",
"entity_id": "D030342",
"entity_type": "Disease",
"text_name": "genetic change"
}
] | [
"p53",
"p53"
] | [
"rhabdomyosarcomas",
"genetic change"
] |
9066351 | Transthyretin amyloidosis: a new mutation associated with dementia. | Familial transthyretin (TTR) amyloidosis commonly presents with peripheral neuropathy and involvement of visceral organs. In contrast, signs of central nervous system (CNS) involvement are exceptional. We report that members of a kindred affected by a slowly progressive dementia, seizures, ataxia, hemiparesis, and decreased vision without neuropathy have TTR amyloid deposits in the leptomeninges, the brain parenchyma, and the eye. This condition, previously labeled oculoleptomeningeal amyloidosis, is linked to a mutation at codon 30 of TTR gene, resulting in the substitution of valine with glycine in this family, TTR amyloid deposits were present in the leptomeninges, especially the leptomeningeal vessels, and in the subependymal regions of the ventricular system where they disrupted the ependymal lining and resulted in amyloid-glial formations protruding into and narrowing the ventricular system. Hydrocephalus and atrophy and infarction of cerebral and cerebellar cortexes were also present. Review of the literature shows that amyloid deposition in the leptomeninges is not uncommon in TTR amyloidoses clinically characterized by peripheral neuropathy and lack of CNS signs. The present kindred, which presented exclusively with signs of CNS involvement, expands the phenotype of TTR amyloidosis and raises questions concerning the mechanisms determining phenotypic expression in TTR familial amyloidosis. | [
{
"begin_idx": "0",
"end_idx": "25",
"entity_id": "C567782",
"entity_type": "Disease",
"text_name": "Transthyretin amyloidosis"
},
{
"begin_idx": "97",
"end_idx": "108",
"entity_id": "D000686",
"entity_type": "Disease",
"text_name": "amyloidosis"
},
{
"begin_idx":... | [
"Yes",
"No"
] | [
false,
true
] | [
{
"begin_idx": "77",
"end_idx": "90",
"entity_id": "7276",
"entity_type": "Gene",
"text_name": "transthyretin"
},
{
"begin_idx": "610",
"end_idx": "613",
"entity_id": "7276",
"entity_type": "Gene",
"text_name": "TTR"
}
] | [
{
"begin_idx": "0",
"end_idx": "25",
"entity_id": "C567782",
"entity_type": "Disease",
"text_name": "Transthyretin amyloidosis"
},
{
"begin_idx": "132",
"end_idx": "153",
"entity_id": "D010523",
"entity_type": "Disease",
"text_name": "peripheral neuropathy"
}
] | [
"transthyretin",
"TTR"
] | [
"Transthyretin amyloidosis",
"peripheral neuropathy"
] |
9066583 | N-acetylation polymorphism in patients with lung cancer and its association with p53 gene mutation. | We determined the polymorphic N-acetyltransferase 2 (NAT2) genotype of 124 patients with non-small-cell lung cancer (NSCLC) and 376 control subjects using a PCR-based assay. The slow acetylator genotype was present in 17 (14%) of 124 NSCLC patients and in 40 (11%) of 376 control subjects. The relative risk of slow acetylators compared with rapid acetylators in patients with adenocarcinoma was 2.01 (p = 0.05). This trend was more marked when the analysis was confined to patients under the age of 65 (relative risk, 2.7; p = 0.03). No such trend was identified in patients with squamous cell carcinoma. We also determined the incidence of p53 gene mutations to investigate the possibility of a link between this gene mutation and N-acetylation polymorphism. There was no significant association between p53 gene mutations and NAT2 polymorphism in the overall NSCLC group. However, the incidence of p53 mutations in adenocarcinoma patients under the age of 65 who had the slow acetylator genotype was 63% compared with 38% in patients with the rapid or intermediate acetylator genotype. These findings suggest that the slow acetylator phenotype may be linked to the impaired metabolism of a carcinogen that predisposes individuals to p53 gene mutations, and thus may be associated with an increased risk of pulmonary adenocarcinoma. | [
{
"begin_idx": "477",
"end_idx": "491",
"entity_id": "D000230",
"entity_type": "Disease",
"text_name": "adenocarcinoma"
},
{
"begin_idx": "1018",
"end_idx": "1032",
"entity_id": "D000230",
"entity_type": "Disease",
"text_name": "adenocarcinoma"
},
{
"begin_idx": "... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "81",
"end_idx": "84",
"entity_id": "7157",
"entity_type": "Gene",
"text_name": "p53"
},
{
"begin_idx": "130",
"end_idx": "151",
"entity_id": "10",
"entity_type": "Gene",
"text_name": "N-acetyltransferase 2"
}
] | [
{
"begin_idx": "44",
"end_idx": "55",
"entity_id": "D008175",
"entity_type": "Disease",
"text_name": "lung cancer"
},
{
"begin_idx": "334",
"end_idx": "339",
"entity_id": "D002289",
"entity_type": "Disease",
"text_name": "NSCLC"
}
] | [
"p53",
"N-acetyltransferase 2"
] | [
"lung cancer",
"NSCLC"
] |
9067760 | E380D: a novel point mutation of CYP21 in an HLA-homozygous patient with salt-losing congenital adrenal hyperplasia due to 21-hydroxylase deficiency. | [
{
"begin_idx": "73",
"end_idx": "148",
"entity_id": "C535979",
"entity_type": "Disease",
"text_name": "salt-losing congenital adrenal hyperplasia due to 21-hydroxylase deficiency"
},
{
"begin_idx": "33",
"end_idx": "38",
"entity_id": "1589",
"entity_type": "Gene",
"text_n... | [
"Yes"
] | [
true
] | [
{
"begin_idx": "33",
"end_idx": "38",
"entity_id": "1589",
"entity_type": "Gene",
"text_name": "CYP21"
}
] | [
{
"begin_idx": "73",
"end_idx": "148",
"entity_id": "C535979",
"entity_type": "Disease",
"text_name": "salt-losing congenital adrenal hyperplasia due to 21-hydroxylase deficiency"
}
] | [
"CYP21"
] | [
"salt-losing congenital adrenal hyperplasia due to 21-hydroxylase deficiency"
] | |
9084930 | Association analysis of CA repeat polymorphism of the endothelial nitric oxide synthase gene with essential hypertension in Japanese. | The nitric oxide synthase (NOS) gene is thought to be associated with essential hypertension (EH), because NO is implicated in endothelium-mediated vasodilation. We investigated the possible association between the alleles of simple tandem repeat DNA polymorphism of the endothelial constitutive NOS (cNOS) gene and EH in Japanese subjects. In all, 100 patients with EH and 123 subjects with normal blood pressure were studied. Polymerase chain reaction was used to amplify the CA repeat site in the endothelial cNOS gene and alleles based on the CA repeat number were determined. The allele frequencies in the hypertensive group and normotensive group were then compared. Twenty-three alleles were identified in this study of Japanese subjects. The overall distributions of allele frequencies in the two groups were not significantly different. However, comparing the allele frequencies in the EH group without left ventricular hypertrophy (LVH) and the normotensive group, the overall distributions were significantly different (p = 0.019). The 33-repeat allele was found more frequently in the EH group without LVH than in the normotensive group (p = 0.000047, Odds ratio = 3.71). In conclusion, the 33-repeat allele of the endothelial cNOS gene is associated with EH without LVH, and may be a genetic marker of EH in Japanese subjects. | [
{
"begin_idx": "108",
"end_idx": "120",
"entity_id": "D006973",
"entity_type": "Disease",
"text_name": "hypertension"
},
{
"begin_idx": "214",
"end_idx": "226",
"entity_id": "D006973",
"entity_type": "Disease",
"text_name": "hypertension"
},
{
"begin_idx": "745",
... | [
"Yes",
"No"
] | [
false,
true
] | [
{
"begin_idx": "417",
"end_idx": "433",
"entity_id": "4846",
"entity_type": "Gene",
"text_name": "constitutive NOS"
},
{
"begin_idx": "435",
"end_idx": "439",
"entity_id": "4846",
"entity_type": "Gene",
"text_name": "cNOS"
}
] | [
{
"begin_idx": "108",
"end_idx": "120",
"entity_id": "D006973",
"entity_type": "Disease",
"text_name": "hypertension"
},
{
"begin_idx": "1248",
"end_idx": "1251",
"entity_id": "D017379",
"entity_type": "Disease",
"text_name": "LVH"
}
] | [
"constitutive NOS",
"cNOS"
] | [
"hypertension",
"LVH"
] |
9090523 | Tay-Sachs disease-causing mutations and neutral polymorphisms in the Hex A gene. | Tay-Sachs disease is an autosomal recessive disorder affecting the central nervous system. The disorder results from mutations in the gene encoding the alpha-subunit of beta-hexosaminidase A, a lysosomal enzyme composed of alpha and beta polypeptides. Seventy-eight mutations in the Hex A gene have been described and include 65 single base substitutions, one large and 10 small deletions, and two small insertions. Because these mutations cripple the catalytic activity of beta-hexosaminidase to varying degrees, Tay-Sachs disease displays clinical heterogeneity. Forty-five of the single base substitutions cause missense mutations; 39 of these are disease causing, three are benign but cause a change in phenotype, and three are neutral polymorphisms. Six nonsense mutations and 14 splice site lesions result from single base substitutions, and all but one of the splice site lesions cause a severe form of Tay-Sachs disease. Eight frameshift mutations arise from six deletion- and two insertion-type lesions. One of these insertions, consisting of four bases within exon 11, is found in 80% of the carriers of Tay-Sachs disease from the Ashkenazi Jewish population, an ethnic group that has a 10-fold higher gene frequency for a severe form of the disorder than the general population. A very large deletion, 7.5 kilobases, including all of exon 1 and portions of DNA upstream and downstream from that exon, is the major mutation found in Tay-Sachs disease carriers from the French Canadian population, a geographic isolate displaying an elevated carrier frequency. Most of the other mutations are confined to single pedigrees. Identification of these mutations has permitted more accurate carrier information, prenatal diagnosis, and disease prognosis. In conjunction with a precise tertiary structure of the enzyme, these mutations could be used to gain insight into the structure-function relationships of the lysosomal enzyme. | [
{
"begin_idx": "0",
"end_idx": "17",
"entity_id": "D013661",
"entity_type": "Disease",
"text_name": "Tay-Sachs disease"
},
{
"begin_idx": "81",
"end_idx": "98",
"entity_id": "D013661",
"entity_type": "Disease",
"text_name": "Tay-Sachs disease"
},
{
"begin_idx": "5... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "69",
"end_idx": "74",
"entity_id": "3073",
"entity_type": "Gene",
"text_name": "Hex A"
},
{
"begin_idx": "555",
"end_idx": "574",
"entity_id": "10724",
"entity_type": "Gene",
"text_name": "beta-hexosaminidase"
}
] | [
{
"begin_idx": "0",
"end_idx": "17",
"entity_id": "D013661",
"entity_type": "Disease",
"text_name": "Tay-Sachs disease"
},
{
"begin_idx": "0",
"end_idx": "17",
"entity_id": "D013661",
"entity_type": "Disease",
"text_name": "Tay-Sachs disease"
}
] | [
"Hex A",
"beta-hexosaminidase"
] | [
"Tay-Sachs disease",
"Tay-Sachs disease"
] |
9096355 | A common mutational pattern in Cockayne syndrome patients from xeroderma pigmentosum group G: implications for a second XPG function. | Xeroderma pigmentosum (XP) patients have defects in nucleotide excision repair (NER), the versatile repair pathway that removes UV-induced damage and other bulky DNA adducts. Patients with Cockayne syndrome (CS), another rare sun-sensitive disorder, are specifically defective in the preferential removal of damage from the transcribed strand of active genes, a process known as transcription-coupled repair. These two disorders are usually clinically and genetically distinct, but complementation analyses have assigned a few CS patients to the rare XP groups B, D, or G. The XPG gene encodes a structure-specific endonuclease that nicks damaged DNA 3' to the lesion during NER. Here we show that three XPG/CS patients had mutations that would produce severely truncated XPG proteins. In contrast, two sibling XPG patients without CS are able to make full-length XPG, but with a missense mutation that inactivates its function in NER. These results suggest that XPG/CS mutations abolish interactions required for a second important XPG function and that it is the loss of this second function that leads to the CS clinical phenotype. | [
{
"begin_idx": "120",
"end_idx": "123",
"entity_id": "C562593",
"entity_type": "Disease",
"text_name": "XPG"
},
{
"begin_idx": "711",
"end_idx": "714",
"entity_id": "C562593",
"entity_type": "Disease",
"text_name": "XPG"
},
{
"begin_idx": "838",
"end_idx": "84... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "120",
"end_idx": "123",
"entity_id": "2073",
"entity_type": "Gene",
"text_name": "XPG"
},
{
"begin_idx": "998",
"end_idx": "1001",
"entity_id": "2073",
"entity_type": "Gene",
"text_name": "XPG"
}
] | [
{
"begin_idx": "120",
"end_idx": "123",
"entity_id": "C562593",
"entity_type": "Disease",
"text_name": "XPG"
},
{
"begin_idx": "966",
"end_idx": "968",
"entity_id": "D003057",
"entity_type": "Disease",
"text_name": "CS"
}
] | [
"XPG",
"XPG"
] | [
"XPG",
"CS"
] |
9100224 | Fabry disease: thirty-five mutations in the alpha-galactosidase A gene in patients with classic and variant phenotypes. | BACKGROUND: Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, results from mutations in the alpha-galactosidase A (alpha-Gal A) gene located at Xq22.1. To determine the nature and frequency of the molecular lesions causing the classical and milder variant Fabry phenotypes and for precise carrier detection, the alpha-Gal A lesions in 42 unrelated Fabry hemizygotes were determined. MATERIALS AND METHODS: Genomic DNA was isolated from affected probands and their family members. The seven alpha-galactosidase A exons and flanking intronic sequences were PCR amplified and the nucleotide sequence was determined by solid-phase direct sequencing. RESULTS: Two patients with the mild cardiac phenotype had missense mutations, I9IT and F113L, respectively. In 38 classically affected patients, 33 new mutations were identified including 20 missense (MIT, A31V, H46R, Y86C, L89P, D92Y, C94Y, A97V, R100T, Y134S, G138R, A143T, S148R, G163V, D170V, C202Y, Y216D, N263S, W287C, and N298S), two nonsense (Q386X, W399X), one splice site mutation (IVS4 + 2T-->C), and eight small exonic insertions or deletions (304del1, 613del9, 777del1, 1057del2, 1074del2, 1077del1, 1212del3, and 1094ins1), which identified exon 7 as a region prone to gene rearrangements. In addition, two unique complex rearrangements consisting of contiguous small insertions and deletions were found in exons 1 and 2 causing L45R/H46S and L120X, respectively. CONCLUSIONS: These studies further define the heterogeneity of mutations causing Fabry disease, permit precise carrier identification and prenatal diagnosis in these families, and facilitate the identification of candidates for enzyme replacement therapy. | [
{
"begin_idx": "0",
"end_idx": "13",
"entity_id": "D000795",
"entity_type": "Disease",
"text_name": "Fabry disease"
},
{
"begin_idx": "132",
"end_idx": "145",
"entity_id": "D000795",
"entity_type": "Disease",
"text_name": "Fabry disease"
},
{
"begin_idx": "491",
... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "44",
"end_idx": "65",
"entity_id": "2717",
"entity_type": "Gene",
"text_name": "alpha-galactosidase A"
},
{
"begin_idx": "258",
"end_idx": "269",
"entity_id": "2717",
"entity_type": "Gene",
"text_name": "alpha-Gal A"
}
] | [
{
"begin_idx": "491",
"end_idx": "508",
"entity_id": "D000795",
"entity_type": "Disease",
"text_name": "Fabry hemizygotes"
},
{
"begin_idx": "150",
"end_idx": "203",
"entity_id": "D008661",
"entity_type": "Disease",
"text_name": "X-linked inborn error of glycosphingolipid... | [
"alpha-galactosidase A",
"alpha-Gal A"
] | [
"Fabry hemizygotes",
"X-linked inborn error of glycosphingolipid catabolism"
] |
9100625 | Linkage and association of insulin gene VNTR regulatory polymorphism with polycystic ovary syndrome. | BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting up to 10% of women of reproductive age. Women with anovulatory PCOS have hyperinsulinaemia, insulin resistance, and dyslipidaemia, and the syndrome is associated with greatly increased risks of non-insulin-dependent diabetes mellitus and cardiovascular disease and it often clusters in families. The VNTR (variable number of tandem repeats) locus upstream of the insulin gene (INS) regulates insulin expression. We have studied INS VNTR as a candidate genetic locus for susceptibility to PCOS. METHODS: We evaluated linkage of PCOS to the INS VNTR locus on chromosome 11p15.5 in 17 families with several cases, and looked for an association between VNTR and PCOS in two additional clinic populations. VNTR genotypes were designated I/I, I/III, and III/III and linkage disequilibrium mapping was used to test the primary role of the VNTR. FINDINGS: In a group of PCOS/male pattern baldness families, we obtained positive evidence for linkage to 11p15.5 (p = 0.002). The INS VNTR III/III genotype was associated with an increased risk of PCOS in two independent case-control studies (odds ratios 8.20 [p = 0.005] and 5.70 [p = 0.043]). Multilocus linkage disequilibrium mapping suggests that VNTR itself is the predisposing locus. INTERPRETATION: Mapping of susceptibility to PCOS to the INS VNTR implies that PCOS is due, in part, to an inherited alteration in insulin production. The data suggest a mechanistic link between type 2 diabetes and PCOS, which is a risk factor for diabetes later in life. | [
{
"begin_idx": "1067",
"end_idx": "1075",
"entity_id": "D000505",
"entity_type": "Disease",
"text_name": "baldness"
},
{
"begin_idx": "425",
"end_idx": "447",
"entity_id": "D002318",
"entity_type": "Disease",
"text_name": "cardiovascular disease"
},
{
"begin_idx":... | [
"Yes",
"No"
] | [
true,
false
] | [
{
"begin_idx": "27",
"end_idx": "34",
"entity_id": "3630",
"entity_type": "Gene",
"text_name": "insulin"
},
{
"begin_idx": "1547",
"end_idx": "1554",
"entity_id": "3630",
"entity_type": "Gene",
"text_name": "insulin"
}
] | [
{
"begin_idx": "74",
"end_idx": "99",
"entity_id": "D011085",
"entity_type": "Disease",
"text_name": "polycystic ovary syndrome"
},
{
"begin_idx": "1618",
"end_idx": "1626",
"entity_id": "D003920",
"entity_type": "Disease",
"text_name": "diabetes"
}
] | [
"insulin",
"insulin"
] | [
"polycystic ovary syndrome",
"diabetes"
] |
9118049 | Erythropoietin reduces anemia and transfusions after chemotherapy with paclitaxel and carboplatin. | BACKGROUND: The authors report on anemia observed during preoperative paclitaxel and carboplatin chemotherapy in patients with advanced head and neck carcinoma and discuss how the use of recombinant human erythropoietin (r-HuEPO) ameliorates this anemia, reducing the need for subsequent packed red blood cell (PRBC) transfusions. METHODS: Response to r-HuEPO was defined as reduced hemoglobin fall during preoperative chemotherapy and reduced transfusion requirements during surgery. Thirty-six patients with advanced head and neck carcinoma were evaluable after treatment with preoperative chemotherapy using paclitaxel and carboplatin. Group 1 was comprised of 14 patients who empirically received r-HuEPO at a dose of 150 U/kg 3 times per week for 3 weeks; in patients deemed nonresponders, the dose was increased to 300 U/kg and 450 U/kg in the subsequent courses. Group 2 was comprised of 22 patients who did not receive r-HuEPO. RESULTS: During preoperative chemotherapy, the mean hemoglobin fall was 0.5 g/dL in Group 1 (P = 0.40). In Group 2 there was a statistically significant mean hemoglobin fall of 3.3 g/dL (P < 0.0001). There was also a nonstatistically significant trend toward fewer PRBC transfusions: none of 14 patients (0%) in Group 1 versus 4 of 22 patients (18%) in Group 2 (P = 0.141). CONCLUSIONS: A significant fall in hemoglobin and an increase in the need for transfusions were observed in head and neck carcinoma patients receiving carboplatin and paclitaxel chemotherapy prior to surgery. Empiric r-HuEPO therapy appeared to prevent anemia and reduced the need for PRBC transfusions. | [
{
"begin_idx": "23",
"end_idx": "29",
"entity_id": "D000740",
"entity_type": "Disease",
"text_name": "anemia"
},
{
"begin_idx": "133",
"end_idx": "139",
"entity_id": "D000740",
"entity_type": "Disease",
"text_name": "anemia"
},
{
"begin_idx": "346",
"end_idx":... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "0",
"end_idx": "14",
"entity_id": "2056",
"entity_type": "Gene",
"text_name": "Erythropoietin"
},
{
"begin_idx": "304",
"end_idx": "318",
"entity_id": "2056",
"entity_type": "Gene",
"text_name": "erythropoietin"
}
] | [
{
"begin_idx": "23",
"end_idx": "29",
"entity_id": "D000740",
"entity_type": "Disease",
"text_name": "anemia"
},
{
"begin_idx": "235",
"end_idx": "258",
"entity_id": "D006258",
"entity_type": "Disease",
"text_name": "head and neck carcinoma"
}
] | [
"Erythropoietin",
"erythropoietin"
] | [
"anemia",
"head and neck carcinoma"
] |
9118321 | Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. | Dopamine is believed to play a major role in the manifestation of attention deficit hyperactivity disorder (ADHD), which affects 3-6% of school-age children and shows evidence of familiarity. The dopamine D4 receptor, which is preferentially distributed in cortical and limbic regions of the brain, is currently of major interest because of the high degree of functionally relevant variability in its gene (DRD4), and the association of this gene with Novelty Seeking behavior. We examined the variability in the length of a region of DRD4 that contains a 48-bp repeat sequence in children with ADHD and controls matched for ethnicity. ADHD children differed from controls in that the 7-fold repeat form of DRD4 occurred significantly more frequently than in the control sample. This form of the receptor has previously been shown to mediate a blunted intracellular response to dopamine. Although ADHD is likely to be multifactorial in its etiology and its heritability is likely to be polygenetic, the present findings suggest that polymorphic variation in the gene encoding the D4 dopamine receptor may be a contributing factor in the expression of symptoms associated with ADHD. | [
{
"begin_idx": "58",
"end_idx": "98",
"entity_id": "D001289",
"entity_type": "Disease",
"text_name": "attention deficit hyperactivity disorder"
},
{
"begin_idx": "166",
"end_idx": "206",
"entity_id": "D001289",
"entity_type": "Disease",
"text_name": "attention deficit hyp... | [
"Yes"
] | [
true
] | [
{
"begin_idx": "0",
"end_idx": "20",
"entity_id": "1815",
"entity_type": "Gene",
"text_name": "Dopamine D4 receptor"
}
] | [
{
"begin_idx": "58",
"end_idx": "98",
"entity_id": "D001289",
"entity_type": "Disease",
"text_name": "attention deficit hyperactivity disorder"
}
] | [
"Dopamine D4 receptor"
] | [
"attention deficit hyperactivity disorder"
] |
9129962 | Gender-specific nonrandom association between the alpha 1-antichymotrypsin and apolipoprotein E polymorphisms in the general population and its implication for the risk of Alzheimer's disease. | A common polymorphism in the alpha 1-antichymotrypsin (ACT) gene has been found co modify the APOE*4-associated risk of Alzheimer's disease due to an apparent interaction between the two loci. This study was undertaken to determine the gender- and age-related distributions of these two polymorphisms in two large population-based samples of Caucasians (n = 803) and Nigerian Blacks (n = 730). Significantly higher frequencies of the ACT*A (78.6% vs. 48.4%; P < 0.001) and APOE*4 (25.6% vs. 15.6%; P < 0.001) alleles were observed in Nigerian Blacks than in Caucasians. In Caucasian women but not in men, the frequency of the APOE*4 allele was significantly lower in the ACT/AA genotype as compared to the ACT/AT and ACT/TT genotypes, while a reverse trend was seen for the APOE*3 allele frequency among the ACT genotypes. The distribution of the ACT*A allele between the APOE*4 carriers and non-APOE*4 carriers was also different in Caucasian women but not in men. A similar gender-specific nonrandom association between the two polymorphisms was observed in Black women but this was not as strong as observed in Caucasian women. When the two samples were stratified by age group, an association or trend of association was observed in all age groups in women only. These data indicate the existence of a nonrandom association between the APOE and ACT loci in women which may have an important implication for the higher prevalence of Alzheimer's disease in women. | [
{
"begin_idx": "172",
"end_idx": "191",
"entity_id": "D000544",
"entity_type": "Disease",
"text_name": "Alzheimer's disease"
},
{
"begin_idx": "313",
"end_idx": "332",
"entity_id": "D000544",
"entity_type": "Disease",
"text_name": "Alzheimer's disease"
},
{
"begin... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "79",
"end_idx": "95",
"entity_id": "348",
"entity_type": "Gene",
"text_name": "apolipoprotein E"
},
{
"begin_idx": "50",
"end_idx": "74",
"entity_id": "12",
"entity_type": "Gene",
"text_name": "alpha 1-antichymotrypsin"
}
] | [
{
"begin_idx": "172",
"end_idx": "191",
"entity_id": "D000544",
"entity_type": "Disease",
"text_name": "Alzheimer's disease"
},
{
"begin_idx": "313",
"end_idx": "332",
"entity_id": "D000544",
"entity_type": "Disease",
"text_name": "Alzheimer's disease"
}
] | [
"apolipoprotein E",
"alpha 1-antichymotrypsin"
] | [
"Alzheimer's disease",
"Alzheimer's disease"
] |
9137812 | Renal cell carcinomas in trichloroethene (TRI) exposed persons are associated with somatic mutations in the von Hippel-Lindau (VHL) tumour suppressor gene. | Renal cell carcinomas (RCC) develop as a consequence of somatic mutations of the von Hippel-Lindau (VHL) tumour suppressor gene. Recent epidemiological studies show that high and prolonged occupational exposures to trichloroethene (TRI) are associated with an increased incidence of RCC. Tumour tissues from 23 RCC patients with occupational histories of very high TRI exposure were analysed for somatic mutations within the VHL gene. DNA was isolated from microdissected tumour cells, amplified by polymerase chain reaction (PCR), and analysed in single strand conformation polymorphism (SSCP) and sequencing. RCC tissues of all 23 TRI exposed persons analysed thus far showed aberrations of the VHL gene, with 30% having aberrations in exon 1, 44% in exon 2, and 26% in exon 3. By comparison to much lower reported VHL mutation frequencies of 33-55% in TRI-unexposed RCC patients, these results indicate a specifically high mutation frequency at the VHL gene in TRI-exposed RCC patients; four of these aberrations have thus far been confirmed as VHL mutations by sequence analysis. This finding indicates the VHL gene being a susceptible and specific target in TRI induced renal carcinogenesis. Furthermore, the frequent involvement of exon 2 identifies potential 'hot spots' for this carcinogen. In addition to the available epidemiological studies the results are now further proof for human renal carcinogenicity induced by high occupational exposures to TRI. | [
{
"begin_idx": "0",
"end_idx": "21",
"entity_id": "D002292",
"entity_type": "Disease",
"text_name": "Renal cell carcinomas"
},
{
"begin_idx": "156",
"end_idx": "177",
"entity_id": "D002292",
"entity_type": "Disease",
"text_name": "Renal cell carcinomas"
},
{
"begi... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "127",
"end_idx": "130",
"entity_id": "7428",
"entity_type": "Gene",
"text_name": "VHL"
},
{
"begin_idx": "127",
"end_idx": "130",
"entity_id": "7428",
"entity_type": "Gene",
"text_name": "VHL"
}
] | [
{
"begin_idx": "0",
"end_idx": "21",
"entity_id": "D002292",
"entity_type": "Disease",
"text_name": "Renal cell carcinomas"
},
{
"begin_idx": "237",
"end_idx": "267",
"entity_id": "D006623",
"entity_type": "Disease",
"text_name": "von Hippel-Lindau (VHL) tumour"
}
] | [
"VHL",
"VHL"
] | [
"Renal cell carcinomas",
"von Hippel-Lindau (VHL) tumour"
] |
9144439 | Insulin gene region contributes to genetic susceptibility to, but may not to low incidence of, insulin-dependent diabetes mellitus in Japanese. | In the Caucasian population, it has been demonstrated that the insulin gene (INS) region contains the insulin-dependent diabetes mellitus locus (IDDM2). In the Japanese population, however, there has been no report demonstrating the contribution of IDDM2 to the pathogenesis of IDDM. We conducted an association study of IDDM in a large number of Japanese subjects with multiple polymorphisms in INS region. We found a significant association of the INS region with IDDM. Alleles positively associated with IDDM in INS region were the same as those positively-associated with IDDM in Caucasian population, although positively-associated alleles are very common (allele frequencies > 0.9) in the Japanese general population. These data suggest that IDDM2 is involved in the genetic susceptibility to IDDM in Japanese. The high frequencies of disease-associated alleles in the general population suggest that IDDM2 locus is not responsible for the low incidence of IDDM in Japanese. | [
{
"begin_idx": "95",
"end_idx": "130",
"entity_id": "D003922",
"entity_type": "Disease",
"text_name": "insulin-dependent diabetes mellitus"
},
{
"begin_idx": "246",
"end_idx": "281",
"entity_id": "D003922",
"entity_type": "Disease",
"text_name": "insulin-dependent diabete... | [
"Yes"
] | [
true
] | [
{
"begin_idx": "0",
"end_idx": "7",
"entity_id": "3630",
"entity_type": "Gene",
"text_name": "Insulin"
}
] | [
{
"begin_idx": "95",
"end_idx": "130",
"entity_id": "D003922",
"entity_type": "Disease",
"text_name": "insulin-dependent diabetes mellitus"
}
] | [
"Insulin"
] | [
"insulin-dependent diabetes mellitus"
] |
9150358 | Cellular localisation of the ataxia-telangiectasia (ATM) gene product and discrimination between mutated and normal forms. | The recently cloned gene (ATM) mutated in the human genetic disorder ataxia-telangiectasia (A-T) is involved in DNA damage response at different cell cycle checkpoints and also appears to have a wider role in signal transduction. Antibodies prepared against peptides from the predicted protein sequence detected a approximately 350 kDa protein corresponding to the open reading frame, which was absent in 13/23 A-T homozygotes. Subcellular fractionation, immunoelectronmicroscopy and immunofluorescence showed that the ATM protein is present in the nucleus and cytoplasmic vesicles. This distribution did not change after irradiation. We also provide evidence that ATM protein binds to p53 and this association is defective in A-T cells compatible with the defective p53 response in these cells. These results provide further support for a role for the ATM protein as a sensor of DNA damage and in a more general role in cell signalling, compatible with the broader phenotype of the syndrome. | [
{
"begin_idx": "192",
"end_idx": "213",
"entity_id": "D001260",
"entity_type": "Disease",
"text_name": "ataxia-telangiectasia"
},
{
"begin_idx": "215",
"end_idx": "218",
"entity_id": "D001260",
"entity_type": "Disease",
"text_name": "A-T"
},
{
"begin_idx": "534",
... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "29",
"end_idx": "56",
"entity_id": "472",
"entity_type": "Gene",
"text_name": "ataxia-telangiectasia (ATM)"
},
{
"begin_idx": "809",
"end_idx": "812",
"entity_id": "7157",
"entity_type": "Gene",
"text_name": "p53"
}
] | [
{
"begin_idx": "192",
"end_idx": "213",
"entity_id": "D001260",
"entity_type": "Disease",
"text_name": "ataxia-telangiectasia"
},
{
"begin_idx": "850",
"end_idx": "853",
"entity_id": "D001260",
"entity_type": "Disease",
"text_name": "A-T"
}
] | [
"ataxia-telangiectasia (ATM)",
"p53"
] | [
"ataxia-telangiectasia",
"A-T"
] |
9150729 | Mutations of the CD40 ligand gene in 13 Japanese patients with X-linked hyper-IgM syndrome. | X-linked hyper-IgM syndrome (XHIM) is a rare primary immunodeficiency caused by a defective CD40 ligand. We identified mutations of the CD40 ligand gene in 13 unrelated Japanese XHIM patients. Of the four patients with missense mutations, one had a mutation within the transmembrane domain, and the three others had mutations affecting the TNF homology region of the extracellular domain. Two of the missense mutations resulted in the substitution of amino acids that are highly conserved in TNF family proteins. Three patients had nonsense mutations, all of which resulted in the truncation of the TNF homology domain of the CD40 ligand. Three patients had genomic DNA deletions of 2, 3 or 4 nucleotides, respectively. All of the deletions were flanked by direct repeat sequences, suggesting that these deletions were caused by slipped mispairing. Three patients had mutations within introns resulting in altered splicing, and multiple splicing products were found in one patient. Thus, each of the 13 Japanese patients had different mutations, 9 of them being novel mutations. These results indicate that mutations in XHIM are highly heterogeneous, although codon 140 seems to be a hot spot of the CD40 ligand gene since two additional point mutations were located at Trp 140, bringing the total numbers of mutations affecting codon 140 to six. In one XHIM family with a missense mutation, prenatal diagnosis was performed by single-strand conformation polymorphism analysis of genomic DNA of a male fetus. | [
{
"begin_idx": "137",
"end_idx": "161",
"entity_id": "D007153",
"entity_type": "Disease",
"text_name": "primary immunodeficiency"
},
{
"begin_idx": "63",
"end_idx": "90",
"entity_id": "D053307",
"entity_type": "Disease",
"text_name": "X-linked hyper-IgM syndrome"
},
{... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "17",
"end_idx": "28",
"entity_id": "959",
"entity_type": "Gene",
"text_name": "CD40 ligand"
},
{
"begin_idx": "228",
"end_idx": "232",
"entity_id": "958",
"entity_type": "Gene",
"text_name": "CD40"
}
] | [
{
"begin_idx": "63",
"end_idx": "90",
"entity_id": "D053307",
"entity_type": "Disease",
"text_name": "X-linked hyper-IgM syndrome"
},
{
"begin_idx": "92",
"end_idx": "119",
"entity_id": "D053307",
"entity_type": "Disease",
"text_name": "X-linked hyper-IgM syndrome"
}
] | [
"CD40 ligand",
"CD40"
] | [
"X-linked hyper-IgM syndrome",
"X-linked hyper-IgM syndrome"
] |
9179433 | Aspirin-induced asthma and HLA-DRB1 and HLA-DPB1 genotypes. | BACKGROUND: Aspirin-induced asthma (AIA) affects one in 10 individuals with adult-onset asthma. It is not known if aspirin sensitivity is due to immune mechanisms or to interference with biochemical pathways. OBJECTIVE: The study aimed to test for possible involvement of the genes of the Major Histocompatibility Complex (MHC) in AIA. METHODS: HLA-DPB1 and HLA-DRB1 genotyping was carried out by DNA methods in 59 patients with positive challenge tests for AIA and in 48 normal and 57 asthmatic controls. RESULTS: The DPB1*0301 frequency was increased in AIA patients when compared with normal controls (19.5% vs 5.2%, Odds Ratio = 4.4, 95% Confidence Interval (CI) 1.6-12.1, P = 0.002), and compared with asthmatic controls (4.4%, OR = 5.3, 95% CI = 1.9-14.4, P = 0.0001). The frequency of DPB1*0401 in AIA subjects was decreased when compared with normal controls (28.8% vs 49.0%, OR = 0.42, 95% CI = 0.24-0.74, P = 0.003) and asthmatic controls (45.6%, OR = 0.48, 95% CI = 0.28-0.83, P = 0.008). The results remained significant when corrected for multiple comparisons. There were no significant HLA-DRB1 associations with AIA. CONCLUSION: The presence of an HLA association suggests that immune recognition of an unknown antigen may be part of the aetiology of AIA. | [
{
"begin_idx": "88",
"end_idx": "94",
"entity_id": "D001249",
"entity_type": "Disease",
"text_name": "asthma"
},
{
"begin_idx": "148",
"end_idx": "154",
"entity_id": "D001249",
"entity_type": "Disease",
"text_name": "asthma"
},
{
"begin_idx": "40",
"end_idx": ... | [
"Yes",
"No"
] | [
false,
false
] | [
{
"begin_idx": "40",
"end_idx": "48",
"entity_id": "3115",
"entity_type": "Gene",
"text_name": "HLA-DPB1"
},
{
"begin_idx": "418",
"end_idx": "426",
"entity_id": "3123",
"entity_type": "Gene",
"text_name": "HLA-DRB1"
}
] | [
{
"begin_idx": "88",
"end_idx": "94",
"entity_id": "D001249",
"entity_type": "Disease",
"text_name": "asthma"
},
{
"begin_idx": "88",
"end_idx": "94",
"entity_id": "D001249",
"entity_type": "Disease",
"text_name": "asthma"
}
] | [
"HLA-DPB1",
"HLA-DRB1"
] | [
"asthma",
"asthma"
] |
9184656 | Interleukin (IL)-1 beta and IL-1 beta mRNA expression in normal and diseased skeletal muscle assessed by immunocytochemistry, immunoblotting and reverse transcriptase-nested polymerase chain reaction. | To confirm the production of IL-1 beta and to optimize detection and semiquantitation of IL-1 beta mRNA by polymerase chain reaction (PCR) techniques in skeletal muscle tissue, immunocytochemistry, immunoblotting and several procedures of RNA extraction and reverse transcription (RT)-PCR amplification were used on muscle samples from 12 patients with conditions associated with local production of IL-1 beta (AZT myopathy: 6 patients; sarcoid myopathy: 6 patients) and from 9 patients with normal muscle used as controls. Abundant IL-1 beta immunoreactivities, corresponding to both pro IL-1 beta and mature IL-1 beta as assessed by immunoblotting, were observed in all diseased muscles, either in inflammatory cells (sarcoid myopathy) or in atrophic muscle fibers (AZT myopathy). Acid guanidinium isothiocyanate phenol-chloroform extraction of RNA appeared less efficient for IL-1 beta mRNA detection by RT-PCR than proteinase K digestion followed by phenol-chloroform extraction. Even using the latter procedure, RT-single PCR for IL-1 beta mRNA was puzzlingly negative in all cases but one; in contrast, RT-nested PCR specified by DNA enzyme immunoassay yielded detection of IL-1 beta mRNA in all diseased muscles and in occasional controls, including the expected PCR product of 391 bp, but also another product of 935 bp, corresponding to IL-1 beta mRNA with unsplicing of the fourth intron. Semi-quantitative PCR showed that production of IL-1 beta mRNA was higher in sarcoid myopathy than in AZT myopathy, and in AZT myopathy than in controls. In conclusion, IL-1 beta expression can be reliably studied using immunocytochemistry, but assessment of IL-1 beta mRNA production in muscle tissue requires optimized extraction and RT-PCR procedures. | [
{
"begin_idx": "616",
"end_idx": "624",
"entity_id": "D009135",
"entity_type": "Disease",
"text_name": "myopathy"
},
{
"begin_idx": "638",
"end_idx": "654",
"entity_id": "D009135",
"entity_type": "Disease",
"text_name": "sarcoid myopathy"
},
{
"begin_idx": "921",
... | [
"Yes"
] | [
true
] | [
{
"begin_idx": "0",
"end_idx": "23",
"entity_id": "3553",
"entity_type": "Gene",
"text_name": "Interleukin (IL)-1 beta"
}
] | [
{
"begin_idx": "945",
"end_idx": "967",
"entity_id": "D009135",
"entity_type": "Disease",
"text_name": "atrophic muscle fibers"
}
] | [
"Interleukin (IL)-1 beta"
] | [
"atrophic muscle fibers"
] |
9189907 | Allelic variability in D21S11, but not in APP or APOE, is associated with cognitive decline in Down syndrome. | Genetic variation in the APOE gene and variation in chromosome 21 genotypes, including the APP locus, may influence age-associated cognitive decline in adults with Down syndrome. Molecular genetic and longitudinal neuropsychological analysis was performed for 41 unrelated Caucasian individuals (mean age 48.1 +/- 1.1 years (s.c.m.)) with free trisomy 21. Allele frequencies and genotype distributions were compared among subgroups with or without evidence of cognitive decline. Genetic variability at APOE and APP was not significantly associated with evidence of cognitive decline. However, aged individuals with Down syndrome, without evidence of cognitive decline, demonstrated unusual allelic variability at D21S11. These findings are discussed in the context of current hypotheses of Alzheimer-type dementia in Down syndrome and in the general population. | [
{
"begin_idx": "900",
"end_idx": "923",
"entity_id": "D000544",
"entity_type": "Disease",
"text_name": "Alzheimer-type dementia"
},
{
"begin_idx": "74",
"end_idx": "108",
"entity_id": "D003072",
"entity_type": "Disease",
"text_name": "cognitive decline in Down syndrome"
... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "49",
"end_idx": "53",
"entity_id": "348",
"entity_type": "Gene",
"text_name": "APOE"
},
{
"begin_idx": "612",
"end_idx": "616",
"entity_id": "348",
"entity_type": "Gene",
"text_name": "APOE"
}
] | [
{
"begin_idx": "274",
"end_idx": "287",
"entity_id": "D004314",
"entity_type": "Disease",
"text_name": "Down syndrome"
},
{
"begin_idx": "760",
"end_idx": "777",
"entity_id": "D003072",
"entity_type": "Disease",
"text_name": "cognitive decline"
}
] | [
"APOE",
"APOE"
] | [
"Down syndrome",
"cognitive decline"
] |
9195224 | Nine novel L1 CAM mutations in families with X-linked hydrocephalus. | Mutations in the gene for neural cell adhesion molecule L1 are responsible for the highly variable phenotype found in families with X-linked hydrocephalus, MASA syndrome, and spastic paraplegia type I. To date, 32 different mutations have been observed, the majority being unique to individual families. Here, we report nine novel mutations in L1 in 10 X-linked hydrocephalus families. Four mutations truncate the L1 protein and eliminate cell surface expression, and two would produce abnormal L1 through alteration of RNA processing. A further two of these mutations are small in-frame deletions that have occurred through a mechanism involving tandem repeated sequences. Together with a single missense mutation, these latter examples contribute to the growing number of existing mutations that affect short regions of the L1 protein that may have particular functional significance. | [
{
"begin_idx": "45",
"end_idx": "67",
"entity_id": "C536078",
"entity_type": "Disease",
"text_name": "X-linked hydrocephalus"
},
{
"begin_idx": "201",
"end_idx": "223",
"entity_id": "C536078",
"entity_type": "Disease",
"text_name": "X-linked hydrocephalus"
},
{
"b... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "95",
"end_idx": "127",
"entity_id": "3897",
"entity_type": "Gene",
"text_name": "neural cell adhesion molecule L1"
},
{
"begin_idx": "11",
"end_idx": "17",
"entity_id": "3897",
"entity_type": "Gene",
"text_name": "L1 CAM"
}
] | [
{
"begin_idx": "45",
"end_idx": "67",
"entity_id": "C536078",
"entity_type": "Disease",
"text_name": "X-linked hydrocephalus"
},
{
"begin_idx": "244",
"end_idx": "269",
"entity_id": "D015419",
"entity_type": "Disease",
"text_name": "spastic paraplegia type I"
}
] | [
"neural cell adhesion molecule L1",
"L1 CAM"
] | [
"X-linked hydrocephalus",
"spastic paraplegia type I"
] |
9196614 | Correlation of clinical, endocrine and molecular abnormalities with in vivo responses to high-dose testosterone in patients with partial androgen insensitivity syndrome. | OBJECTIVE: To investigate the responses of two patients previously diagnosed as Reifenstein's syndrome to graded high-dose testosterone in terms of hormone levels, nitrogen balance and sebum secretion and to attempt to correlate these parameters with the properties of their androgen receptors and mutations in the androgen receptor gene. DESIGN: Nitrogen balance was determined by comparing controlled nitrogen intake to the amount excreted. Sebum excretion was measured on the forehead. Patients were studied during control periods (no treatment) and during administration of testosterone propionate. Blood samples were used as a source of genomic DNA and to measure peripheral hormone levels; androgen receptor binding was determined using genital skin fibroblasts. PATIENTS: Two patients of XY karyotype, with ambiguous external genitalia and problems of testicular descent who had required mastectomy as teenagers. Normal male controls of proven fertility. MEASUREMENTS: Nitrogen balance, sebum excretion rate and peripheral hormone levels (testosterone, dihydrotestosterone, LH and FSH) were studied before and after testosterone therapy (1 or 5 mg/kg/day). Genomic DNA was extracted from peripheral blood leucocytes and regions of the androgen receptor gene amplified by polymerase chain reaction using pairs of specific primers. Mobility of amplified DNA from patients was analysed on denaturing gradient acrylamide gels and fragments differing in mobility from those of normal controls were sequenced. Fibroblasts were cultured from scrotal skin biopsies and androgen receptor binding parameters, subcellular localization and up-regulation were determined. RESULTS: Testosterone therapy resulted in raised plasma testosterone, dihydrotestosterone and oestradiol in both patients. In patient 1 (lesser genital abnormality), LH was suppressed by 5 mg/kg/day testosterone to the upper limit of the normal range but FSH remained low normal. Both LH and FSH were suppressed by testosterone treatment in patient 2 (greater genital abnormality). Nitrogen retention was increased in both patients (4.2 and 3.0 g/24 h respectively); sebum excretion rate increased to normal in patient 1 but showed no change in patient 2. Mutations in the androgen receptor gene were identified in both patients. In patient 1 a single nucleotide change from adenosine to guanosine resulted in the substitution of glycine for glutamic acid at position 772 within the hormone binding domain of the receptor. In patient 2 a single nucleotide mutation from guanosine to adenosine resulted in the substitution of lysine for arginine at position 608 (exon 3) situated in the second zinc finger of the DNA binding domain. Both patients had a normal number of androgen binding sites in genital skin fibroblasts but those in patient 1 showed reduced binding affinity and rapid dissociation of receptor/ligand complexes while those in patient 2 showed defective nuclear localization. CONCLUSION: In patients with partial androgen insensitivity syndrome the type of androgen receptor mutation and responses to short-term androgen treatment can be correlated with the individual's potential to virilize. If there is a mutation in the androgen receptor DNA binding domain the patient may show little ability to virilize either spontaneously at puberty or after androgen treatment. Sebum excretion appears to be more discriminating than nitrogen balance or gonadotrophin suppression as an index of tissue response to androgens. | [
{
"begin_idx": "984",
"end_idx": "1012",
"entity_id": "D012734",
"entity_type": "Disease",
"text_name": "ambiguous external genitalia"
},
{
"begin_idx": "129",
"end_idx": "168",
"entity_id": "D013734",
"entity_type": "Disease",
"text_name": "partial androgen insensitivity... | [
"Yes",
"No"
] | [
true,
false
] | [
{
"begin_idx": "485",
"end_idx": "502",
"entity_id": "367",
"entity_type": "Gene",
"text_name": "androgen receptor"
},
{
"begin_idx": "1738",
"end_idx": "1755",
"entity_id": "367",
"entity_type": "Gene",
"text_name": "androgen receptor"
}
] | [
{
"begin_idx": "129",
"end_idx": "168",
"entity_id": "D013734",
"entity_type": "Disease",
"text_name": "partial androgen insensitivity syndrome"
},
{
"begin_idx": "984",
"end_idx": "1012",
"entity_id": "D012734",
"entity_type": "Disease",
"text_name": "ambiguous external ... | [
"androgen receptor",
"androgen receptor"
] | [
"partial androgen insensitivity syndrome",
"ambiguous external genitalia"
] |
9200673 | Evaluation of a Cys23Ser mutation within the human 5-HT2C receptor gene: no evidence for an association of the mutant allele with obesity or underweight in children, adolescents and young adults. | Serotonin is a neurotransmitter involved in a large number of psychophysiological processes including the regulation of mood, arousal, aggression, sleep, learning, nociceptions, nerve growth and importantly, appetitive functions. Alterations of 5-HT receptor activity have been shown to occur in many psychiatric diseases including depression, anxiety, eating disorders, schizophrenia etc. Hence, genetic variation in genes coding for serotonin receptor proteins might well be involved in the genetic predisposition to these diseases and therefore are of great pharmacogenetic relevance. Knockout mice deficient of a functional 5-HT2C receptor have implicated a potential role of this receptor subtype in the serotonergic control of appetite. A Cys23Ser mutation in the human 5-HT2C receptor gene discovered recently prompted us to investigate this mutation with regard to the development of human obesity. We have evaluated this mutation in 241 obese children and adolescents (mean BMI > or = 97th percentile), 80 normal weight children (BMI 5th-85th percentile) and 92 underweight probands (BMI < or = 15th percentile) for a possible association with obesity. The frequencies of the mutant allele in all three weight groups (obese subjects: 0.1597; normal weight: 0.168; underweight: 0.1575) were very similar. Association as well as linkage studies were negative. Therefore it is unlikely that this receptor mutation plays a direct role in the development of human obesity. | [
{
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"end_idx": "547",
"entity_id": "D001008",
"entity_type": "Disease",
"text_name": "anxiety"
},
{
"begin_idx": "549",
"end_idx": "565",
"entity_id": "D001068",
"entity_type": "Disease",
"text_name": "eating disorders"
},
{
"begin_idx": "497",
... | [
"Yes",
"No"
] | [
true,
false
] | [
{
"begin_idx": "51",
"end_idx": "66",
"entity_id": "3358",
"entity_type": "Gene",
"text_name": "5-HT2C receptor"
},
{
"begin_idx": "824",
"end_idx": "839",
"entity_id": "3358",
"entity_type": "Gene",
"text_name": "5-HT2C receptor"
}
] | [
{
"begin_idx": "130",
"end_idx": "137",
"entity_id": "D009765",
"entity_type": "Disease",
"text_name": "obesity"
},
{
"begin_idx": "567",
"end_idx": "580",
"entity_id": "D012559",
"entity_type": "Disease",
"text_name": "schizophrenia"
}
] | [
"5-HT2C receptor",
"5-HT2C receptor"
] | [
"obesity",
"schizophrenia"
] |
9202122 | Congenital leptin deficiency is associated with severe early-onset obesity in humans. | The extreme obesity of the obese (ob/ob) mouse is attributable to mutations in the gene encoding leptin, an adipocyte-specific secreted protein which has profound effects on appetite and energy expenditure. We know of no equivalent evidence regarding leptin's role in the control of fat mass in humans. We have examined two severely obese children who are members of the same highly consanguineous pedigree. Their serum leptin levels were very low despite their markedly elevated fat mass and, in both, a homozygous frame-shift mutation involving the deletion of a single guanine nucleotide in codon 133 of the gene for leptin was found. The severe obesity found in these congenitally leptin-deficient subjects provides the first genetic evidence that leptin is an important regulator of energy balance in humans. | [
{
"begin_idx": "0",
"end_idx": "28",
"entity_id": "D003677",
"entity_type": "Disease",
"text_name": "Congenital leptin deficiency"
},
{
"begin_idx": "67",
"end_idx": "74",
"entity_id": "D009765",
"entity_type": "Disease",
"text_name": "obesity"
},
{
"begin_idx": "... | [
"Yes",
"No"
] | [
true,
false
] | [
{
"begin_idx": "183",
"end_idx": "189",
"entity_id": "3952",
"entity_type": "Gene",
"text_name": "leptin"
},
{
"begin_idx": "838",
"end_idx": "844",
"entity_id": "3952",
"entity_type": "Gene",
"text_name": "leptin"
}
] | [
{
"begin_idx": "98",
"end_idx": "118",
"entity_id": "D009765",
"entity_type": "Disease",
"text_name": "obesity of the obese"
},
{
"begin_idx": "0",
"end_idx": "28",
"entity_id": "D003677",
"entity_type": "Disease",
"text_name": "Congenital leptin deficiency"
}
] | [
"leptin",
"leptin"
] | [
"obesity of the obese",
"Congenital leptin deficiency"
] |
9204966 | A novel threonine --> proline mutation at the end of 2B rod domain in the keratin 2e chain in ichthyosis bullosa of Siemens. | We report a novel mutation in a case of ichthyosis bullosa of Siemens that results in a threonine --> proline substitution in a novel location, codon 485 in a highly conserved residue position of the IATYRKLLEGE consensus motif at the end of the 2B rod domain segment of the keratin 2e chain. The disease phenotype is consistent with the inappropriate substitution of a proline near the end of the rod domain, because it lies near the predicted molecular overlap region of coiled-coil molecules, which is critical for the maintenance of the structural integrity of keratin intermediate filaments. | [
{
"begin_idx": "94",
"end_idx": "123",
"entity_id": "D053560",
"entity_type": "Disease",
"text_name": "ichthyosis bullosa of Siemens"
},
{
"begin_idx": "165",
"end_idx": "194",
"entity_id": "D053560",
"entity_type": "Disease",
"text_name": "ichthyosis bullosa of Siemens"
... | [
"Yes"
] | [
true
] | [
{
"begin_idx": "74",
"end_idx": "84",
"entity_id": "3849",
"entity_type": "Gene",
"text_name": "keratin 2e"
}
] | [
{
"begin_idx": "94",
"end_idx": "123",
"entity_id": "D053560",
"entity_type": "Disease",
"text_name": "ichthyosis bullosa of Siemens"
}
] | [
"keratin 2e"
] | [
"ichthyosis bullosa of Siemens"
] |
9208814 | Male pseudohermaphroditism resulting from a novel mutation in the human steroid 5 alpha-reductase type 2 gene (SRD5A2). | The enzyme steroid 5 alpha-reductase, via NADPH, catalyses the conversion of testosterone to dihydrotestosterone, which is required for the embryonic differentiation of the external male genitalia and the prostate. An impairment of this reaction causes a form of male pseudohermaphroditism in which genetic males differentiate predominantly as phenotypic females. Molecular analysis of the 5 alpha-reductase type 2 gene in a patient with confirmed biochemical 5 alpha-reductase deficiency has resulted in the identification of a novel mutation, GAA to AAA, at codon 200. This mutation produces an amino acid change from glutamic acid to lysine, and may affect the ability of the enzyme to bind its co-factor. | [
{
"begin_idx": "582",
"end_idx": "608",
"entity_id": "C535830",
"entity_type": "Disease",
"text_name": "alpha-reductase deficiency"
},
{
"begin_idx": "0",
"end_idx": "26",
"entity_id": "D058490",
"entity_type": "Disease",
"text_name": "male pseudohermaphroditism"
},
{... | [
"Yes",
"No"
] | [
false,
true
] | [
{
"begin_idx": "111",
"end_idx": "117",
"entity_id": "6716",
"entity_type": "Gene",
"text_name": "SRD5A2"
},
{
"begin_idx": "510",
"end_idx": "527",
"entity_id": "6715",
"entity_type": "Gene",
"text_name": "5 alpha-reductase"
}
] | [
{
"begin_idx": "582",
"end_idx": "608",
"entity_id": "C535830",
"entity_type": "Disease",
"text_name": "alpha-reductase deficiency"
},
{
"begin_idx": "383",
"end_idx": "409",
"entity_id": "D058490",
"entity_type": "Disease",
"text_name": "male pseudohermaphroditism"
}
] | [
"SRD5A2",
"5 alpha-reductase"
] | [
"alpha-reductase deficiency",
"male pseudohermaphroditism"
] |
9218152 | Insulin receptor substrate-1 gene polymorphism and cardiovascular risk in non-insulin dependent diabetes mellitus and patients undergoing coronary angiography. | Clustering of risk factors for cardiovascular disease related to insulin resistance may account for the increased incidence of vascular disease in these conditions and in non-diabetic subjects. To investigate the relationship between a coding polymorphism in the insulin receptor substrate-1 gene and the presence of cardiovascular risk factors, 209 patients with NIDDM and 452 subjects investigated for coronary artery disease (CAD) were studied. In the NIDDM subjects 22 (10.5%) were heterozygous at codon 972 for a polymorphism which codes for a glycine to arginine substitution and 187 (89.5%) were homozygous for the wild type. Patients with the mutation had lower levels of cholesterol compared with wild type (mean, 95% confidence intervals), 5.3 (4.9-5.8) vs 6.0 (5.9-6.2) mmol/l, respectively (P = 0.002), triglyceride 1.7 (1.4-2.1) vs 2.2 (2.0-2.4) mmol/l (P = 0.051), factor VII:C activity 109.5 (85.5-133.5) vs 133.5 (127-140)% (P = 0.057) and PAI-1 antigen, 16.0 (10.5-24.3) vs 22.2 (20.0-24.6) ng/ml (P = 0.054). There were no differences in body mass index, indices of glycaemic control, fasting insulin or the prevalence of hypertension. In patients with CAD, 55 (12.7%) were carriers of the mutation (including three homozygotes) (NIDDM vs CAD, NS). Although similar trends in cholesterol, factor VII, PAI-1 antigen and triglyceride existed between carriers of the mutation and the wild type, none reached statistical significance. The results indicate that the IRS-1 gene is not implicated in the pathogenesis of NIDDM or CAD. | [
{
"begin_idx": "191",
"end_idx": "213",
"entity_id": "D002318",
"entity_type": "Disease",
"text_name": "cardiovascular disease"
},
{
"begin_idx": "564",
"end_idx": "587",
"entity_id": "D003324",
"entity_type": "Disease",
"text_name": "coronary artery disease"
},
{
... | [
"Yes",
"No"
] | [
true,
false
] | [
{
"begin_idx": "0",
"end_idx": "28",
"entity_id": "3667",
"entity_type": "Gene",
"text_name": "Insulin receptor substrate-1"
},
{
"begin_idx": "1479",
"end_idx": "1484",
"entity_id": "5054",
"entity_type": "Gene",
"text_name": "PAI-1"
}
] | [
{
"begin_idx": "74",
"end_idx": "113",
"entity_id": "D003924",
"entity_type": "Disease",
"text_name": "non-insulin dependent diabetes mellitus"
},
{
"begin_idx": "1422",
"end_idx": "1424",
"entity_id": "D056770",
"entity_type": "Disease",
"text_name": "NS"
}
] | [
"Insulin receptor substrate-1",
"PAI-1"
] | [
"non-insulin dependent diabetes mellitus",
"NS"
] |
9222170 | Genetic association of the low-density lipoprotein receptor-related protein gene (LRP), an apolipoprotein E receptor, with late-onset Alzheimer's disease. | The presence of the APOE epsilon 4 allele encoding apolipoprotein E4 (apoE4) is the major genetic risk factor for late-onset Alzheimer's disease (AD). However, the molecular and cellular mechanisms by which APOE epsilon 4 renders AD risk are unclear. In this report, we present genetic evidence that an apoE receptor, LRP, may be associated with the expression of late-onset AD. Using a biallelic genetic marker in exon 3 of LRP, late-onset AD cases markedly differed from the control subjects in the distribution of LRP genotypes, and this difference was highly accentuated among AD cases with positive family history of senile dementia. Furthermore, the numbers of neutritic plaques were significantly altered as a consequence of different LRP genotypes in postmortem AD cases. Taken together, our results implicate the pathophysiology of LRP in the expression of late-onset AD. | [
{
"begin_idx": "134",
"end_idx": "153",
"entity_id": "D000544",
"entity_type": "Disease",
"text_name": "Alzheimer's disease"
},
{
"begin_idx": "280",
"end_idx": "299",
"entity_id": "D000544",
"entity_type": "Disease",
"text_name": "Alzheimer's disease"
},
{
"begin... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "206",
"end_idx": "223",
"entity_id": "348",
"entity_type": "Gene",
"text_name": "apolipoprotein E4"
},
{
"begin_idx": "672",
"end_idx": "675",
"entity_id": "4035",
"entity_type": "Gene",
"text_name": "LRP"
}
] | [
{
"begin_idx": "134",
"end_idx": "153",
"entity_id": "D000544",
"entity_type": "Disease",
"text_name": "Alzheimer's disease"
},
{
"begin_idx": "530",
"end_idx": "532",
"entity_id": "D000544",
"entity_type": "Disease",
"text_name": "AD"
}
] | [
"apolipoprotein E4",
"LRP"
] | [
"Alzheimer's disease",
"AD"
] |
9222757 | Identification of mutations causing 6-pyruvoyl-tetrahydropterin synthase deficiency in four Italian families. | 6-Pyruvoyl-tetrahydrobiopterin synthase (PTPS) is involved in tetrahydrobiopterin (BH4) biosynthesis, the cofactor for various enzymes including the hepatic phenylalanine hydroxylase. Inherited PTPS deficiency leads to BH4 depletion, causes hyperphenylalaninemia, and requires cofactor replacement therapy for treatment. We previously isolated the human PTPS cDNA and recently characterized its corresponding gene, PTS. Here we developed PCR-based mutation analysis with newly designed primers to detect genomic alterations and describe five mutations, four of which are novel, in the PTS gene of four Italian families with affected individuals. The mutant alleles found included three missense mutations (T67M, K129E, D136V), a previously described triplet deletion (delta V57), and a single c-3-->g transversion in the 3'-acceptor splice site of intron 1, leading to cryptic splice site usage that resulted in a 12 bp deletion (mutant allele delta (K29-S32)). Except for K129E, all mutant alleles were inactive and/or unstable proteins, as shown by recombinant expression and Western blot analysis of patients' fibroblasts. The PTPS-deficient patient with the homozygous K129E allele had transient hyperphenylalaninemia, did not depend on BH4 replacement therapy, and showed normal PTPS immunoreactivity, but no enzyme activity in primary fibroblasts and red blood cells. In contrast to its inactivity in these cells, the K129E mutant was 2-3 fold more active than wild-type PTPS when transfected into COS-1 or the human hepatoma cell line Hep G2. K129E appears thus as a mutant PTPS whose activity depends on the cell type. | [
{
"begin_idx": "1240",
"end_idx": "1254",
"entity_id": "C535325",
"entity_type": "Disease",
"text_name": "PTPS-deficient"
},
{
"begin_idx": "1633",
"end_idx": "1658",
"entity_id": "D002292",
"entity_type": "Disease",
"text_name": "hepatoma cell line Hep G2"
},
{
"... | [
"Yes",
"No"
] | [
true,
false
] | [
{
"begin_idx": "110",
"end_idx": "149",
"entity_id": "5805",
"entity_type": "Gene",
"text_name": "6-Pyruvoyl-tetrahydrobiopterin synthase"
},
{
"begin_idx": "1587",
"end_idx": "1591",
"entity_id": "5805",
"entity_type": "Gene",
"text_name": "PTPS"
}
] | [
{
"begin_idx": "1240",
"end_idx": "1254",
"entity_id": "C535325",
"entity_type": "Disease",
"text_name": "PTPS-deficient"
},
{
"begin_idx": "294",
"end_idx": "319",
"entity_id": "D030342",
"entity_type": "Disease",
"text_name": "Inherited PTPS deficiency"
}
] | [
"6-Pyruvoyl-tetrahydrobiopterin synthase",
"PTPS"
] | [
"PTPS-deficient",
"Inherited PTPS deficiency"
] |
9231050 | A CTLA-4 gene polymorphism is associated with both Graves disease and autoimmune hypothyroidism. | OBJECTIVE: The autoimmune thyroid diseases, Graves disease and autoimmune hypothyroidism, result from a complex interaction between genetic, environmental and endogenous factors. The genetic loci conferring susceptibility remain unclear. A recent report has demonstrated an association between a microsatellite polymorphism of the CTLA-4 gene (allele 106) on chromosome 2q33 and Graves' disease in Caucasian patients in the USA. The aim of the present study was to confirm this association in UK patients and to determine whether this polymorphism is also associated with autoimmune hypothyroidism. DESIGN: Analysis of Caucasian patients with autoimmune thyroid disease from a single clinic, compared to local Caucasian controls. PATIENTS: We studied 112 patients with Graves' disease, 44 with autoimmune hypothyroidism and 91 controls. MEASUREMENTS: CTLA-4 microsatellite gene polymorphisms were determined by polymerase chain reaction amplification of genomic DNA and resolution of the products on sequencing gels. RESULTS: As in previous studies, 21 alleles of the CTLA-4 microsatellite region were detected. Allele 106 was significantly increased in patients with Graves' disease (P = 0.006) and in those with autoimmune hypothyroidism (P = 0.02) when compared to controls. There was no significant difference between the groups in the distribution of the other alleles and no association between allele 106 and sex, HLA-DR or -DQ specificities or the presence of ophthalmopathy in the Graves' patients. CONCLUSIONS: These results confirm that the CTLA-4 gene, or one closely associated with it, confers susceptibility to Grave's disease but is not specific as the CTLA-4 106 allele is also associated with autoimmune hypothyroidism. This association seems to be with autoimmune thyroid disease in general. | [
{
"begin_idx": "70",
"end_idx": "95",
"entity_id": "C562768",
"entity_type": "Disease",
"text_name": "autoimmune hypothyroidism"
},
{
"begin_idx": "160",
"end_idx": "185",
"entity_id": "C562768",
"entity_type": "Disease",
"text_name": "autoimmune hypothyroidism"
},
{
... | [
"Yes",
"No"
] | [
true,
false
] | [
{
"begin_idx": "2",
"end_idx": "8",
"entity_id": "1493",
"entity_type": "Gene",
"text_name": "CTLA-4"
},
{
"begin_idx": "428",
"end_idx": "434",
"entity_id": "1493",
"entity_type": "Gene",
"text_name": "CTLA-4"
}
] | [
{
"begin_idx": "476",
"end_idx": "491",
"entity_id": "D006111",
"entity_type": "Disease",
"text_name": "Graves' disease"
},
{
"begin_idx": "740",
"end_idx": "766",
"entity_id": "D013967",
"entity_type": "Disease",
"text_name": "autoimmune thyroid disease"
}
] | [
"CTLA-4",
"CTLA-4"
] | [
"Graves' disease",
"autoimmune thyroid disease"
] |
9241276 | Somatic mutation of the MEN1 gene in parathyroid tumours. | Primary hyperparathyroidism is a common disorder with an annual incidence of approximately 0.5 in 1,000 (ref. 1). In more than 95% of cases, the disease is caused by sporadic parathyroid adenoma or sporadic hyperplasia. Some cases are caused by inherited syndromes, such as multiple endocrine neoplasia type 1 (MEN1; ref. 2). In most cases, the molecular basis of parathyroid neoplasia is unknown. Parathyroid adenomas are usually monoclonal, suggesting that one important step in tumour development is a mutation in a progenitor cell. Approximately 30% of sporadic parathyroid tumours show loss of heterozygosity (LOH) for polymorphic markers on 11q13, the site of the MEN1 tumour suppressor gene. This raises the question of whether such sporadic parathyroid tumours are caused by sequential inactivation of both alleles of the MEN1 gene. We recently cloned the MEN1 gene and identified MEN1 germline mutations in fourteen of fifteen kindreds with familial MEN1 (ref. 10). We have studied parathyroid tumours not associated with MEN1 to determine whether somatic mutations in the MEN1 gene are present. Among 33 tumours we found somatic MEN1 gene mutation in 7, while the corresponding MEN1 germline sequence was normal in each patient. All tumours with MEN1 gene mutation showed LOH on 11q13, making the tumour cells hemi- or homozygous for the mutant allele. Thus, somatic MEN1 gene mutation for the mutant allele. Thus, somatic MEN1 gene mutation contributes to tumorigenesis in a substantial number of parathyroid tumours not associated with the MEN1 syndrome. | [
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"entity_type": "Disease",
"text_name": "sporadic hyperplasia"
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"end_idx": "56",
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"entity_type": "Disease",
"text_name": "parathyroid tumours"
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{
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true
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{
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"end_idx": "28",
"entity_id": "4221",
"entity_type": "Gene",
"text_name": "MEN1"
}
] | [
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"entity_type": "Disease",
"text_name": "multiple endocrine neoplasia type 1"
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{
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"end_idx": "643",
"entity_id": "D009369",
"entity_type": "Disease",
"text_name": "parathyroid tumours"
}... | [
"multiple endocrine neoplasia type 1",
"MEN1"
] | [
"multiple endocrine neoplasia type 1",
"parathyroid tumours"
] |
9272150 | Interaction between obesity and genetic polymorphisms in the apolipoprotein CIII gene and lipoprotein lipase gene on the risk of hypertriglyceridemia in Chinese. | To understand the effects of the interaction between genetic polymorphisms and obesity on the risk of hypertriglyceridemia (HTG), two polymorphisms, an SstI polymorphism on the apolipoprotein CIII gene and a HindIII polymorphism on the lipoprotein lipase gene, were analyzed in 339 Chinese subjects with (82 cases in the HTG group) or without HTG (257 cases in the control group). Our data revealed that the frequencies of obesity, the SstI minor allele (S2), and the HindIII major allele (H+) in the HTG group were significantly higher than in the control group. Subgroup analysis revealed that the association between these two polymorphisms and HTG occurred predominantly in nonobese subjects and in subjects with the less hypertriglyceridemic genotype of another polymorphism. Multivariate logistic regression analysis showed that all three risk factors (obesity, S2-containing chromosome, and H+ homozygosity) were associated with HTG, and an interaction was found between obesity and H+ homozygosity for the occurrence of HTG. The risk of HTG increased significantly with combinations of risk factors. Subjects can be divided into low or high risk groups for HTG using such combinations. These results provide evidence of interaction between obesity and the HindIII polymorphism of the lipoprotein lipase gene on the risk of HTG. | [
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"entity_type": "Disease",
"text_name": "obesity"
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"end_idx": "248",
"entity_id": "D009765",
"entity_type": "Disease",
"text_name": "obesity"
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{
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"end_idx... | [
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] | [
true,
true
] | [
{
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"entity_id": "345",
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"text_name": "apolipoprotein CIII"
},
{
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"end_idx": "416",
"entity_id": "4023",
"entity_type": "Gene",
"text_name": "lipoprotein lipase"
}
] | [
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"begin_idx": "20",
"end_idx": "27",
"entity_id": "D009765",
"entity_type": "Disease",
"text_name": "obesity"
},
{
"begin_idx": "1493",
"end_idx": "1496",
"entity_id": "D015228",
"entity_type": "Disease",
"text_name": "HTG"
}
] | [
"apolipoprotein CIII",
"lipoprotein lipase"
] | [
"obesity",
"HTG"
] |
9291295 | No release of histamine and substance P in capsaicin-induced neurogenic inflammation in intact human skin in vivo: a microdialysis study. | BACKGROUND: Studies in rodents' skin have indicated substance P to be the main inflammatory mediator involved in neurogenic inflammation, acting partly by release of histamine from skin mast cells. The mediators released in neurogenic inflammation in human skin remain to be determined. OBJECTIVES: To determine the effects of intradermally injected and topically applied capsaicin on the release of histamine and substance P and skin responses in intact human skin in vivo. METHODS: Extracellular skin levels of histamine and substance P were measured by microdialysis technique and assayed by enzyme and radio immunoassays. Two kinds of dialysis fibres (210 microm, 2 kDa, and 500 microm, 20 kDa) were inserted intradermally into forearm skin for studies of histamine release to topically administered capsaicin and intradermally injected capsaicin and substance P. RESULTS: Baseline histamine skin levels were 8.0 +/- 0.7 nM. Intradermally injected capsaicin (0.3-30 microM, 7.5-750 pmol) caused significantly and dose-related flare and pain reactions, but no significant histamine release or weals. Intradermally injected substance P (1 and 3 microM, 25 and 75 pmol) released significant amounts of histamine (peak levels being 90 and 475 nM), evoked weal-and-flare reactions, but did not cause pain. Capsaicin 2% ointment, applied on the skin for 2.5 h, increased skin blood flow by 300-400% as measured by laser Doppler flowmetry, elicited a longstanding burning sensation, but did not release histamine. Substance P-like immunoreactivity (SP-LI) was below the 1.8 pM detection limit following insertion of 20 kDa dialysis fibre and after intradermal injection of capsaicin 3 microM. Intradermal injection of injection of 1 microM of substance P increased SP-LI levels to values greater than 4500 pM, confirming the ability of the dialysis fibre to recover this peptide. CONCLUSIONS: Capsaicin-induced neurogenic activation does not involve the release of histamine from mast cells or detectable amounts of substance P release from sensory nerves in normal human skin in vivo. | [
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"entity_type": "Disease",
"text_name": "pain"
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"entity_type": "Disease",
"text_name": "pain"
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] | [
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true
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},
{
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"end_idx": "1004",
"entity_id": "6863",
"entity_type": "Gene",
"text_name": "substance P"
}
] | [
{
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"end_idx": "84",
"entity_id": "D020078",
"entity_type": "Disease",
"text_name": "neurogenic inflammation"
},
{
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"end_idx": "1182",
"entity_id": "D010146",
"entity_type": "Disease",
"text_name": "pain"
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] | [
"substance P (1 and 3",
"substance P"
] | [
"neurogenic inflammation",
"pain"
] |
9294615 | Germline mutation of RET codon 883 in two cases of de novo MEN 2B. | Germline mutations in the RET proto-oncogene are seen in the majority of patients with the dominantly inherited cancer syndromes multiple endocrine neoplasia type 2 (MEN 2). The clinical subtypes of MEN 2 (MEN 2A, MEN 2B and familial MTC) all have medullary thyroid carcinoma, but vary in the involvement of pheochromocytoma, parathyroid adenoma/hyperplasia and developmental abnormalities. A single RET mutation, resulting in the substitution M918T, has been identified in 94% of cases of MEN 2B (which consists of MTC, pheochromocytoma and developmental abnormalities). Here we report the identification of a new germline RET mutation (A883F) in two de novo cases of MEN 2B. Identification of this new mutation will contribute to understanding the molecular basis of MEN 2B, and will assist in the clinical management of families harbouring this mutation. | [
{
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"end_idx": "304",
"entity_id": "C536911",
"entity_type": "Disease",
"text_name": "familial MTC"
},
{
"begin_idx": "429",
"end_idx": "456",
"entity_id": "D006130",
"entity_type": "Disease",
"text_name": "developmental abnormalities"
},
{
"begi... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "59",
"end_idx": "65",
"entity_id": "5979",
"entity_type": "Gene",
"text_name": "MEN 2B"
},
{
"begin_idx": "59",
"end_idx": "65",
"entity_id": "5979",
"entity_type": "Gene",
"text_name": "MEN 2B"
}
] | [
{
"begin_idx": "59",
"end_idx": "65",
"entity_id": "D018814",
"entity_type": "Disease",
"text_name": "MEN 2B"
},
{
"begin_idx": "233",
"end_idx": "238",
"entity_id": "D018813",
"entity_type": "Disease",
"text_name": "MEN 2"
}
] | [
"MEN 2B",
"MEN 2B"
] | [
"MEN 2B",
"MEN 2"
] |
9301478 | Effects of thalidomide and related metabolites in a mouse corneal model of neovascularization. | Thalidomide, when administered orally, is an inhibitor of angiogenesis in the basic fibroblast growth factor (bFGF)-induced rabbit cornea micropocket assay. We now show in the mouse that thalidomide given intraperitoneally but not orally significantly inhibits bFGF-induced and vascular endothelial growth factor (VEGF)-induced corneal neovascularization. We further demonstrate that this inhibition is independent from thalidomide's ability to suppress tumor necrosis factor-alpha (TNF-alpha) production. Experiments examining thalidomide's enantiomers reveal-that the S(-)-enantiomer has the strongest antiangiogenic activity in VEGF-induced and bFGF-induced corneal neovascularization. Structure activity studies suggest that thalidomide's anti-angiogenic activity is related to the open ring metabolites resulting from hydrolysis. Together these data support a correlation between thalidomide's antiangiogenic and teratogenic activities. | [
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"end_idx": "93",
"entity_id": "D015861",
"entity_type": "Disease",
"text_name": "neovascularization"
},
{
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"end_idx": "449",
"entity_id": "D016510",
"entity_type": "Disease",
"text_name": "corneal neovascularization"
},
{
"b... | [
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"Yes",
"No",
"No"
] | [
true,
true,
false,
false
] | [
{
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"end_idx": "407",
"entity_id": "7422",
"entity_type": "Gene",
"text_name": "vascular endothelial growth factor"
},
{
"begin_idx": "205",
"end_idx": "209",
"entity_id": "2247",
"entity_type": "Gene",
"text_name": "bFGF"
},
{
"begin_idx": "373"... | [
{
"begin_idx": "423",
"end_idx": "449",
"entity_id": "D016510",
"entity_type": "Disease",
"text_name": "corneal neovascularization"
},
{
"begin_idx": "423",
"end_idx": "449",
"entity_id": "D016510",
"entity_type": "Disease",
"text_name": "corneal neovascularization"
},
... | [
"vascular endothelial growth factor",
"bFGF",
"vascular endothelial growth factor",
"bFGF"
] | [
"corneal neovascularization",
"corneal neovascularization",
"neovascularization",
"neovascularization"
] |
9302664 | Decreased tumour necrosis factor-beta production in TNFB*2 homozygote: an important predisposing factor of lupus nephritis in Koreans. | Low TNF production and its association with TNF gene restriction fragment length polymorphism (RFLP) was demonstrated in (NZW/NZB) F1 mice. However, little is known about the significance of TNF production in association with TNF gene polymorphism in human SLE. This study was designed to evaluate the role of TNF production of peripheral blood mononuclear cells (PBMC) and its association with TNFB gene polymorphism in SLE, particularly lupus nephritis. TNFB gene polymorphism was defined by PCR-NcoI RFLP. TNF productions of phytohemagglutinin (PHA)-stimulated PBMC and T cells were examined by bioassay using L929 cell line and ELISA. The PBMC stimulated by PHA from patients with SLE (n = 60) tended to secrete less amounts of TNF by bioassay (1032 +/- 184 pg/ml vs 1524 +/- 224 pg/ml, P = 0.094), and TNF-beta by ELISA (P = 0.0082) than that from normal controls (n = 38). The low TNF-alpha producer was more frequent in nephritis than non-nephritis (34.4% vs 7.1% respectively, P < 0.01). TNF-beta also revealed similar results (53.1% vs 21.4%, P < 0.05). In SLE, mean production of TNF-beta was decreased in TNFB*2 homozygote (n = 18) than that in TNFB*1 homozygote (n = 9) (1126.3 +/- 145 pg/ml) vs 642 +/- 118.4 pg/ml, respectively, P = 0.021), whereas TNF-alpha production showed little difference between the two groups (710.1 +/- 56.4 vs 542.4 +/- 71.1 pg/ml, respectively, P = 0.149). Our results demonstrate that decreased TNF production of PBMC, which was significantly associated with TNFB*2 homozygosity, could be an important predisposing factor of lupus nephritis in Koreans. | [
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"end_idx": "142",
"entity_id": "C536657",
"entity_type": "Disease",
"text_name": "TNF"
},
{
"begin_idx": "179",
"end_idx": "182",
"entity_id": "C536657",
"entity_type": "Disease",
"text_name": "TNF"
},
{
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"end_idx": "32... | [
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] | [
true,
true
] | [
{
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"text_name": "TNF-beta"
},
{
"begin_idx": "1398",
"end_idx": "1407",
"entity_id": "7124",
"entity_type": "Gene",
"text_name": "TNF-alpha"
}
] | [
{
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"end_idx": "395",
"entity_id": "D008180",
"entity_type": "Disease",
"text_name": "SLE"
},
{
"begin_idx": "556",
"end_idx": "559",
"entity_id": "D008180",
"entity_type": "Disease",
"text_name": "SLE"
}
] | [
"TNF-beta",
"TNF-alpha"
] | [
"SLE",
"SLE"
] |
9314411 | Association of variants in critical core promoter element of angiotensinogen gene with increased risk of essential hypertension in Japanese. | We examined the association between variants in the core promoter element 1 (AGCE1) of the human angiotensinogen gene (AGT), which acts as a critical regulator of AGT transcription, and the risk for hypertension. One hundred and eighty patients with documented essential hypertension and a family history of hypertension and 194 control subjects without hypertension were selected and frequency matched by age and sex. Genomic DNA from leukocytes was analyzed for genetic variants (position: -20 to -18) in AGCE1. The haplotype in AGCE1 was significantly associated with increased risk of essential hypertension (P<.05). The frequency of subjects with homozygous C allele at position -18(CC/C-18T) was significantly higher in case patients than in control subjects (P<.005), and the evaluated odds ratio for hypertension was 4.2 (95% confidence interval [CI]: 1.4 to 12.8, CC/C-18T versus CT/C-18T). The homozygous threonine allele at codon 235 (TT/M235T) in exon 2 of AGT was also associated with hypertension (P<.02; odds ratio, TT versus other genotypes, 1.8; 95% CI, 1.1 to 2.7). According to haplotype analysis between AGT polymorphisms, we identified linkage disequilibrium between M235T and A-20C and between M235T and C-18T. We conclude that C-18T polymorphism in AGCE1 is a genetic risk factor for essential hypertension in the Japanese and is more tightly and directly associated with hypertension than TT/M235T. | [
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"end_idx": "127",
"entity_id": "D006973",
"entity_type": "Disease",
"text_name": "hypertension"
},
{
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"end_idx": "352",
"entity_id": "D006973",
"entity_type": "Disease",
"text_name": "hypertension"
},
{
"begin_idx": "412",
... | [
"Yes"
] | [
true
] | [
{
"begin_idx": "61",
"end_idx": "76",
"entity_id": "183",
"entity_type": "Gene",
"text_name": "angiotensinogen"
}
] | [
{
"begin_idx": "115",
"end_idx": "127",
"entity_id": "D006973",
"entity_type": "Disease",
"text_name": "hypertension"
}
] | [
"angiotensinogen"
] | [
"hypertension"
] |
9323322 | Association study of schizophrenia and the histidase gene. | Previous findings of increased heterozygosity for histidinemia among schizophrenic patients make the histidase gene a plausible candidate for genetic studies in schizophrenia. In the present study, we used a tetranucleotide repeat polymorphism in intron 8 of the histidase gene to examine the possibility that the histidase gene contributes to the genetic component of schizophrenia. In a first sample of 161 patients and 128 controls, we found the 4 repeat allele to be in excess in the patients. In contrast, the 3 repeat allele was less frequent in patients. A second sample of 95 patients and 93 controls was utilized to test these hypotheses. However, both observations were not replicated. We therefore concluded that our results do not support an involvement of the histidase gene in the development of schizophrenia. | [
{
"begin_idx": "109",
"end_idx": "121",
"entity_id": "C538320",
"entity_type": "Disease",
"text_name": "histidinemia"
},
{
"begin_idx": "21",
"end_idx": "34",
"entity_id": "D012559",
"entity_type": "Disease",
"text_name": "schizophrenia"
},
{
"begin_idx": "128",
... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "43",
"end_idx": "52",
"entity_id": "3034",
"entity_type": "Gene",
"text_name": "histidase"
},
{
"begin_idx": "43",
"end_idx": "52",
"entity_id": "3034",
"entity_type": "Gene",
"text_name": "histidase"
}
] | [
{
"begin_idx": "21",
"end_idx": "34",
"entity_id": "D012559",
"entity_type": "Disease",
"text_name": "schizophrenia"
},
{
"begin_idx": "109",
"end_idx": "121",
"entity_id": "C538320",
"entity_type": "Disease",
"text_name": "histidinemia"
}
] | [
"histidase",
"histidase"
] | [
"schizophrenia",
"histidinemia"
] |
9328472 | A new pathogenic mutation in the APP gene (I716V) increases the relative proportion of A beta 42(43). | We report a novel mutation in the amyloid precursor protein gene (APP I716V) which probably leads to familial early onset Alzheimer's disease with an onset age in the mid 50s. Cells transfected with cDNAs bearing this mutation produce more A beta 1-42(43) than those transfected with wild-type APP and this effect is additive with that of the previously reported APP V717I mutation thus providing a novel approach for further increasing A beta 1-42(43) in model systems. | [
{
"begin_idx": "224",
"end_idx": "243",
"entity_id": "D000544",
"entity_type": "Disease",
"text_name": "Alzheimer's disease"
},
{
"begin_idx": "87",
"end_idx": "93",
"entity_id": "351",
"entity_type": "Gene",
"text_name": "A beta"
},
{
"begin_idx": "342",
"end... | [
"Yes"
] | [
false
] | [
{
"begin_idx": "87",
"end_idx": "93",
"entity_id": "351",
"entity_type": "Gene",
"text_name": "A beta"
}
] | [
{
"begin_idx": "224",
"end_idx": "243",
"entity_id": "D000544",
"entity_type": "Disease",
"text_name": "Alzheimer's disease"
}
] | [
"A beta"
] | [
"Alzheimer's disease"
] |
9342194 | Genetic association between monoamine oxidase and manic-depressive illness: comparison of relative risk and haplotype relative risk data. | There have been several conflicting reports of association of monoamine oxidase (MAO) A gene polymorphisms and bipolar affective disorder. In order to determine the possible role of the MAO region in susceptibility to affective disorders in an independent sample, we have genotyped 83 probands of bipolar affective disorder families, 56 sets of parents of bipolar probands, and 84 normal controls for intronic simple sequence repeat polymorphisms of the MAO-A and MAO-B genes. For MAO-A there were no significant differences in allele frequencies between bipolar and normal control groups for both genders. However, for MAO-B there were significant differences between groups for both genders. In contrast, allele-wise haplotype relative risk analysis for the 56 bipolar proband-parent trios found no significant differences between transmitted and non-transmitted allele frequencies for MAO-A or B. These data do not support the association of MAO-A or B with bipolar affective disorder but do demonstrate that undetected population stratification can be an important source of bias in case-control studies. | [
{
"begin_idx": "50",
"end_idx": "74",
"entity_id": "C564108",
"entity_type": "Disease",
"text_name": "manic-depressive illness"
},
{
"begin_idx": "249",
"end_idx": "275",
"entity_id": "D001714",
"entity_type": "Disease",
"text_name": "bipolar affective disorder"
},
{
... | [
"Yes",
"No"
] | [
false,
true
] | [
{
"begin_idx": "200",
"end_idx": "225",
"entity_id": "4128",
"entity_type": "Gene",
"text_name": "monoamine oxidase (MAO) A"
},
{
"begin_idx": "619",
"end_idx": "624",
"entity_id": "4128",
"entity_type": "Gene",
"text_name": "MAO-A"
}
] | [
{
"begin_idx": "50",
"end_idx": "74",
"entity_id": "C564108",
"entity_type": "Disease",
"text_name": "manic-depressive illness"
},
{
"begin_idx": "356",
"end_idx": "375",
"entity_id": "D019964",
"entity_type": "Disease",
"text_name": "affective disorders"
}
] | [
"monoamine oxidase (MAO) A",
"MAO-A"
] | [
"manic-depressive illness",
"affective disorders"
] |
9347854 | A newly identified pattern of K-ras mutations at codons 12 and 13 is associated with long-term survival in colorectal cancer. | BACKGROUND: Although K-ras mutations reportedly occur in 40% to 60% of all colorectal carcinomas, the relationship between specific mutations and clinical outcome is unclear. The purpose of this study was to assess the frequency and types of K-ras mutations in 89 colorectal cancer patients, comparing groups with short-term (less than 5 years) and long-term (more than 10 years) survival. METHODS: The group was divided into four cohorts by survival and modified Dukes classification (Dukes B2 and C2). DNA was extracted from formalin-fixed paraffin-embedded archival material. Mutational status was analyzed using a modification of allele-specific-polymerase chain reaction. RESULTS: Mutations in codon 12 were found in 11.2% of tumors, and 83% of tumors had mutations in codon 13. Gly > Asp accounted for 85.2% of the mutations. Tumors with mutations in both codon 12 and codon 13 occurred significantly more frequently in the long-term (21.3%) versus the short-term (2.4%) survival group. Gly > Asp mutations in either codon were related to long-term survival, and 80% of long-term survivors with mutations in both codons had Gly > Asp mutations in both. CONCLUSIONS: Simultaneous mutation in codons 12 and 13 of the K-ras gene appears to be a positive prognostic indicator in colorectal cancer. | [
{
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"end_idx": "863",
"entity_id": "D009369",
"entity_type": "Disease",
"text_name": "tumors"
},
{
"begin_idx": "876",
"end_idx": "882",
"entity_id": "D009369",
"entity_type": "Disease",
"text_name": "tumors"
},
{
"begin_idx": "958",
"end_idx... | [
"Yes",
"No"
] | [
true,
false
] | [
{
"begin_idx": "30",
"end_idx": "35",
"entity_id": "3845",
"entity_type": "Gene",
"text_name": "K-ras"
},
{
"begin_idx": "1347",
"end_idx": "1352",
"entity_id": "3845",
"entity_type": "Gene",
"text_name": "K-ras"
}
] | [
{
"begin_idx": "201",
"end_idx": "222",
"entity_id": "D015179",
"entity_type": "Disease",
"text_name": "colorectal carcinomas"
},
{
"begin_idx": "958",
"end_idx": "964",
"entity_id": "D009369",
"entity_type": "Disease",
"text_name": "Tumors"
}
] | [
"K-ras",
"K-ras"
] | [
"colorectal carcinomas",
"Tumors"
] |
9354802 | Mutations in the hminK gene cause long QT syndrome and suppress IKs function. | Ion-channel beta-subunits are ancillary proteins that co-assemble with alpha-subunits to modulate the gating kinetics and enhance stability of multimeric channel complexes. Despite their functional importance, dysfunction of potassium-channel beta-subunits has not been associated with disease. Recent physiological studies suggest that KCNE1 encodes beta-subunits (hminK) that co-assemble with KvLQT1 alpha-subunits to form the slowly activating delayed rectifier K+ (IKs) channel. Because KVLQT1 mutations cause arrhythmia susceptibility in the long QT syndrome (LQT), we hypothesized that mutations in KCNE1 also cause this disorder. Here, we define KCNE1 missense mutations in affected members of two LQT families. Both mutations (S74L, D76N) reduced IKs by shifting the voltage dependence of activation and accelerating channel deactivation. D76N hminK also had a strong dominant-negative effect. The functional consequences of these mutations would be delayed cardiac repolarization and an increased risk of arrhythmia. This is the first description of KCNE1 as an LQT gene and confirms that hminK is an integral protein of the IKs channel. | [
{
"begin_idx": "592",
"end_idx": "602",
"entity_id": "D001145",
"entity_type": "Disease",
"text_name": "arrhythmia"
},
{
"begin_idx": "1092",
"end_idx": "1102",
"entity_id": "D001145",
"entity_type": "Disease",
"text_name": "arrhythmia"
},
{
"begin_idx": "34",
... | [
"Yes",
"No"
] | [
true,
true
] | [
{
"begin_idx": "415",
"end_idx": "420",
"entity_id": "3753",
"entity_type": "Gene",
"text_name": "KCNE1"
},
{
"begin_idx": "1176",
"end_idx": "1181",
"entity_id": "50488",
"entity_type": "Gene",
"text_name": "hminK"
}
] | [
{
"begin_idx": "34",
"end_idx": "50",
"entity_id": "D008133",
"entity_type": "Disease",
"text_name": "long QT syndrome"
},
{
"begin_idx": "783",
"end_idx": "786",
"entity_id": "D008133",
"entity_type": "Disease",
"text_name": "LQT"
}
] | [
"KCNE1",
"hminK"
] | [
"long QT syndrome",
"LQT"
] |
9375852 | Fourteen novel mucopolysaccharidosis IVA producing mutations in GALNS gene. | Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive disorder caused by a deficiency of the lysosomal N-acetylgalactosamine-6-sulfate sulfatase. Here, we report our analysis of data on 21 patients of diverse ethnic and geographic origins studied by SSCP and sequencing analysis. Sixteen mutations were detected, including 14 new mutations (11 missense, one premature termination, one splice site alteration, and one cryptic site alteration). The donor splice site mutation (IVS4 + 1G-->A) predicts that normal splicing will be abolished and that translation would lead to an immediate premature termination (W141X). Another novel nucleotide change outside the coding sequence is an intronic alteration (IVS9-42C-->T:ggtcggtgcggttggtgc) creating a potential cryptic donor site. The nucleotide sequence surrounding this alteration is highly suggestive of a consensus donor splice site. All 12 missense and nonsense mutations were shown by transient expression to abolish or greatly reduce GALNS activity, thereby providing an explanation as to why they produce MPS IVA. All mutations were readily confirmed by restriction enzyme or by allelic specific oligonucleotide analysis (ASO). These findings, coupled with previously reported mutations, bring the total of different mutations to 41 among independent families with MPS IVA, illustrating the extensive allelic heterogeneity among mutations producing MPS IVA. | [
{
"begin_idx": "15",
"end_idx": "40",
"entity_id": "D009085",
"entity_type": "Disease",
"text_name": "mucopolysaccharidosis IVA"
},
{
"begin_idx": "76",
"end_idx": "101",
"entity_id": "D009085",
"entity_type": "Disease",
"text_name": "Mucopolysaccharidosis IVA"
},
{
... | [
"Yes",
"No"
] | [
true,
false
] | [
{
"begin_idx": "64",
"end_idx": "69",
"entity_id": "2588",
"entity_type": "Gene",
"text_name": "GALNS"
},
{
"begin_idx": "1072",
"end_idx": "1077",
"entity_id": "2588",
"entity_type": "Gene",
"text_name": "GALNS"
}
] | [
{
"begin_idx": "159",
"end_idx": "228",
"entity_id": "D009085",
"entity_type": "Disease",
"text_name": "deficiency of the lysosomal N-acetylgalactosamine-6-sulfate sulfatase"
},
{
"begin_idx": "118",
"end_idx": "146",
"entity_id": "D030342",
"entity_type": "Disease",
"tex... | [
"GALNS",
"GALNS"
] | [
"deficiency of the lysosomal N-acetylgalactosamine-6-sulfate sulfatase",
"autosomal recessive disorder"
] |
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