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Studies on Molecular Basis of Wilson Disease by Genetic and Functional Approaches

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Title Studies on Molecular Basis of Wilson Disease by Genetic and Functional Approaches
 
Creator Mukherjee, Shashwata
 
Subject Molecular & Human Genetics
 
Description Wilson disease (WD), an inborn error of copper metabolism, is inherited in an autosomal recessive manner. It is caused due to mutations in ATP7B gene which impair the normal
function of the copper transporting P-type ATPase, resulting in copper accumulation and toxicity leading to hepatic and neuropsychiatric manifestations of WD. This study describes a comprehensive genetic analysis of 199 Indian WD patients including mutations detected
previously from this group, undertakes functional assessment of the nucleotide variants in ATP7B promoter, correlates genotype with disease phenotype and explores the effect of missense mutations on the molecular fate of the protein. The patient cohort harbors a total of 10 common and 48 rare mutations in the coding region of ATP7B including 22 novel changes. The common mutations represent 74% of characterized coding mutant alleles with
p.C271X (63/260) and p.G1101R (7/31) being the most prevalent in East and West Indian patients, respectively. The mutation spectrum between East and West is mostly different with only three mutations (p.G1061E, p.N1270S and p.A1049A-fs) being shared between both the groups. Eight novel and 10 reported variants have been detected in the promoter and non-coding regions (5'- and 3'-UTRs) of ATP7B. Promoter reporter assay demonstrated 5 variants and 1 haplotype to significantly downregulate promoter activity which might interfere with ATP7B gene regulation. The Neurological Involvement Score (NIS) was developed to capture the spectrum of neurological involvement in WD patients. By utilizing the age at onset, NIS and ATP7B mutational background of the patients, a genotype-phenotype
matrix was generated that could be effectively used to depict the phenotypic spectra of WD affected individuals and serve as a platform to identify prospective “outliers”
to be investigated for their remarkable phenotypic divergence. Next, study was conducted to ascertain the cellular localization and anterograde trafficking of GFP fusion constructs for 9 different ATP7B mutants in presence and absence of copper supplementation. While 6 of 9
mutants showed normal behavior, 2 mutants (p.G1061E and p.G1101R) were found to be mislocalized to endoplasmic reticulum and a single mutant (p.S1362A) was unresponsive to
copper induced redistribution suggesting that variant molecular phenotypes of ATP7B are likely to influence the clinical phenotype of WD patients. This effort is precursor to understanding the clinical heterogeneity of WD in the context of molecular events precipitated by the defects in the causal gene.
 
Date 2013
 
Type Thesis
NonPeerReviewed
 
Format application/pdf
application/pdf
 
Identifier http://www.eprints.iicb.res.in/1993/1/Shashwata_Mukherjee_PhD_Thesis.pdf
http://www.eprints.iicb.res.in/1993/4/B_Thesis_Abstract_12Dec13_9pm.pdf
Mukherjee, Shashwata (2013) Studies on Molecular Basis of Wilson Disease by Genetic and Functional Approaches. PhD thesis, Calcutta University.
 
Relation http://www.eprints.iicb.res.in/1993/