Abstract
Wilson disease (WD) is an autosomal recessive disorder, characterized by excessive deposition of copper in various parts of the body, mainly in the liver and brain. It is caused by mutations in ATP7B. We report here the genetic analysis of 102 WD families from a south Indian population. Thirty-six different ATP7B mutations, including 13 novel ones [p.Ala58fs*19, p.Lys74fs*9, p.Gln281*, p.Pro350fs*12, p.Ser481*, p.Leu735Arg, p.Val752Gly, p.Asn812fs*2, p.Val845Ala, p.His889Pro, p.Ile1184fs*1, p.Val1307Glu and p.Ala1339Pro], were identified in 76/102 families. Interestingly, the mutation analysis of affected individuals in two families identified two different homozygous mutations in each family, and thus each affected individual from these families harbored two mutations in each ATP7B allele. Of 36 mutations, 28 were missense, thus making them the most prevalent mutations identified in the present study. Nonsense, insertion and deletion represented 3/36, 2/36 and 3/36 mutations, respectively. The haplotype analysis suggested founder effects for all the 14 recurrent mutations. Our study thus expands the mutational landscape of ATP7B with a total number of 758 mutations. The mutations identified during the present study will facilitate carrier and pre-symptomatic detection, and prenatal genetic diagnosis in affected families.
Highlights
Wilson disease (WD, MIM #277900) is an autosomal recessive disorder, characterized by the excessive deposition of copper in the body, mainly in the liver and brain
3–5 ml of peripheral blood was drawn from each individual in a VacutainerTM EDTA tube (Becton Dickinson, Franklin Lakes, NJ) for genomic DNA isolation, using a WizardTM genomic DNA extraction kit (Promega, Madison, WI)
To determine if the cause of WD in these families is due to ATP7B gene (GenBank accession # NM_000053.3) mutation(s), its entire coding region, including the intron-exon boundaries, was amplified using specific primers (Table B in S1 File)
Summary
Wilson disease (WD, MIM #277900) is an autosomal recessive disorder, characterized by the excessive deposition of copper in the body, mainly in the liver and brain. ATP7B (MIM #606882; ATPase copper transporting beta), the causative gene of WD, is located on the chromosome 13q14.3-q21 [4,5,6] Exons and codes for a 1,465 amino acid long protein of 165 kDa, which contains following domains: six copper binding domains (CBD1-6), eight transmembrane domains (TMS1-8), Adomain and ATP binding domain It shows granular cytoplasmic expression in most tissues (https://www.proteinatlas.org/ENSG00000123191-ATP7B/tissue), and resides mainly in the trans-Golgi network (TGN). We have screened the entire coding region of ATP7B in a large cohort of 102 families from a south Indian population, mainly from the state of Karnataka, and identified 36 different mutations in the gene
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