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Molecular pathogenesis of Wilson disease: haplotype analysis, detection of prevalent mutations and genotype–phenotype correlation in Indian patients

IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata

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Title Molecular pathogenesis of Wilson disease: haplotype analysis, detection of prevalent mutations and genotype–phenotype correlation in Indian patients
 
Creator Gupta, A
Aikath, D
Neogi, R
Datta, S
Basu, K
Maity, B
Trivedi, R
Ray, J
Das, S. K
Gangopadhyay, P. K
Ray, Kunal
 
Subject Molecular & Human Genetics
 
Description Wilson disease (WD) is an autosomal recessive disorder caused by defects in the copper-transporting Ptype ATPase gene (ATP7B) resulting in the accumulation of copper in the liver and the brain. We identified prevalent mutations in the ATP7B of Indian WD patients and attempted to correlate those with the disease phenotype. Patients from 62 unrelated families and their first-degree relatives comprising 200 individuals were enrolled in this study. Three dinucleotide repeat markers flanking WD locus and a few intragenic SNPs were used to determine the genotypes and construct haplotypes of the patients. Seven recurring haplotypes accounting for 58% of the total mutant chromosomes were identified, and four underlying defects in the ATP7B representing 37% of WD chromosomes were detected. In addition, five other rare mutations were characterized. Thus a total of nine mutations including five novel changes were identified in the ATP7B of WD patients. Interestingly, homozygotes for different mutations that would be expected to produce similar defective proteins showed significant disparity in terms of organ involvement and severity of the disease. We also observed WD patients with neurological symptoms with little or no manifestation of hepatic pathogenesis. In one WD family, the proband and a sib had remarkably different phenotypes despite sharing the same pair of mutant chromosomes. These findings suggest a potential role for yet unidentified modifying loci for the observed phenotypic heterogeneity among the WD patients.
 
Date 2005
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/315/1/fuHUMAN_GENETICS__Volume_118_(1)_49%2D57_2005[18].pdf
Gupta, A and Aikath, D and Neogi, R and Datta, S and Basu, K and Maity, B and Trivedi, R and Ray, J and Das, S. K and Gangopadhyay, P. K and Ray, Kunal (2005) Molecular pathogenesis of Wilson disease: haplotype analysis, detection of prevalent mutations and genotype–phenotype correlation in Indian patients. Human Genetics, 118. pp. 49-57.
 
Relation http://dx.doi.org/10.1007/s00439-005-0007-y
http://www.eprints.iicb.res.in/315/