Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein disulfide isomerase (PDI) plays an important role in the endoplasmic reticulum (ER) by facilitating the exchange of disulfide bonds and, together with other ER stress proteins, is induced in amyotrophic lateral sclerosis (ALS). However, genetic polymorphisms in the P4HB gene, which encodes PDI, have not been thoroughly investigated in ALS cases. In this study, we determined whether single-nucleotide polymorphisms (SNPs) in the P4HB gene were associated with familial ALS (FALS) and sporadic ALS (SALS). We report significant genotypic associations for two SNPs in P4HB with FALS, rs876016 (P=0.0198) and rs2070872 (P=0.0046), all values being FDR corrected. Significant allelic associations were also obtained for rs876016 with FALS (P=0.0155) and ALS (FALS and SALS) (P=0.0148). Four SNP haplotypes, which included two additional flanking SNPs, rs876017 and rs8324, were examined and rare haplotypes were found to be more common in ALS cases compared to controls. Seven haplotypes were significantly associated with FALS and one haplotype was significantly associated with SALS. One rare haplotype, which was present in controls, was overrepresented in a group of SOD1-positive FALS cases. Reduced survival was observed in FALS cases possessing at least one copy of the minor allele of rs2070872 (P=0.0059) and rs8324 (P=0.0167) and in individuals lacking the homozygous AAAC/AAAC diplotype (P=0.011). The results suggest that P4HB is a modifier gene in ALS susceptibility and may represent a potential therapeutic target for ALS.
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PMID:Association studies indicate that protein disulfide isomerase is a risk factor in amyotrophic lateral sclerosis. 2333 74

Disruption of endoplasmic reticulum (ER) proteostasis is a salient feature of amyotrophic lateral sclerosis (ALS). Upregulation of ER foldases of the protein disulfide isomerase (PDI) family has been reported in ALS mouse models and spinal cord tissue and body fluids derived from sporadic ALS cases. Although in vitro studies suggest a neuroprotective role of PDIs in ALS, the possible contribution of genetic mutations of these ER foldases in the disease process remains unknown. Interestingly, intronic variants of the PDIA1 gene were recently reported as a risk factor for ALS. Here, we initially screened for mutations in two major PDI genes (PDIA1/P4HB and PDIA3/ERp57) in a US cohort of 96 familial and 96 sporadic ALS patients using direct DNA sequencing. Then, 463 familial and 445 sporadic ALS patients from two independent cohorts were also screened for mutations in these two genes using whole exome sequencing. A total of nine PDIA1 missense variants and seven PDIA3 missense variants were identified in 16 ALS patients. We have identified several novel and rare single nucleotide polymorphisms (SNPs) in both genes that are enriched in ALS cases compared with a large group of control subjects showing a frequency of around 1% in ALS cases. The possible biological and structural impact of these ALS-linked PDI variants is also discussed.
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PMID:Identification of rare protein disulfide isomerase gene variants in amyotrophic lateral sclerosis patients. 2591 42

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease that targets the motor system; it is caused by the loss of motor neurons in the spinal cord, brain stem, and cerebral cortex. However, the etiology of ALS remains unknown, although genetic factors may play an important role in its development. The purpose of this study was to investigate the association between common polymorphisms in protein disulfide isomerase (PDI) with sporadic amyotrophic lateral sclerosis (SALS) in a Chinese Han population. Two single nucleotide polymorphisms (SNPs) in P4HB (rs876016 and rs2070872) were genotyped in 322 patients with SALS and 265 control subjects using polymerase chain reaction-restriction fragment length polymorphism. Our results showed that SNPs rs876016 and rs2070872 were significantly associated with ALS. The minor allele frequencies of rs876016 (C) and rs2070872 (G) were significantly higher in patients with sporadic ALS than in control subjects (P = 0.035 and 0.003, respectively). The genotype frequencies of rs876016 and rs2070872 were significantly different between SALS patients and control subjects (genotypic P < 0.001). Individuals carrying rs876016/ rs2070872 C/G genotypes were associated with a significantly increased risk of SALS. These results suggest that common variants in PDI might contribute to the development of SALS in the Chinese Han population.
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PMID:Polymorphisms in protein disulfide isomerase are associated with sporadic amyotrophic lateral sclerosis in the Chinese Han population. 2637 82