Wilson Disease Mutations in the American Population: Identification of Five Novel Mutations in ATP7B

ABSTRACT

Wilson disease is an autosomal recessive disorder characterized by toxic accumulation of copper in a number of organs such as liver and brain, which results in significant disability or death if left untreated. Wilson disease is caused by mutations in ATP7B, a copper transporter. We analyzed 108 American Wilson disease patients, who are predominantly White, for mutations in ATP7B. Consistent with studies from other populations, H1069Q was the most common mutation in this group of patients, accounting for 40.3% of the sequenced alleles; 26 of the 108 patients were homozygous, and 35 patients were heterozygous for this mutation. We also identified 24 additional ATP7B mutations, of which five were novel. The five new mutations consist of two insertion mutations (2302insT and 3843insT), one splice site mutation (IVS11+2:T>A), one combination of deletion (2bp) and insertion (19bp) (3693-3697delins19bp), and one missense mutation (G1213S). All variants are predicted to be disease-causing mutations. Ninety six percent of all mutations we identified were clustered in regions encoding the C-terminal half (catalytic domain) of the ATP7B protein. Furthermore, we found that 84% of the mutant alleles identified in the American population are located in exons 14 and 18.