Homozygous Mutations in the Conserved ATP Hinge Region of the Wilson Disease Gene

Objective To determine whether any correlation exists between the phenotype and genotype of 2 Lebanese families with members affected with Wilson disease (WD). Background WD is an autosomal-recessive disorder of copper transport with significant phenotypic diversity. Most patients are compound heterozygous making it difficult to establish a clear link between phenotype and genotype. Study We investigated 14 members from 2 Lebanese families (H and Z) with 5 members affected with WD. Mutation analysis of the ATP7B gene, and clinical assessments were carried out for both families. We also performed a literature search retrieving reported phenotypes of all patients homozygous to mutations in any of the 21 exons of the ATP7B. Results Patients of the H and Z-families were found homozygous for the respective Asn1270Ser and Pro1273Leu mutations in the adenosine triphosphate (ATP) hinge region of exon 18. Of the healthy members, 6 were heterozygous and 3 had normal sequences. Clinically, 4 patients had liver cirrhosis and 1 had asymptomatic transaminitis. One of the patients also had neurologic symptoms. Screening the literature for patients homozygous for mutations in the ATP hinge region identified 25 patients including ours. The overall prevalence of the hepatic phenotype among patients homozygous for mutation in exon 18 was 80% and was significantly higher than those in exons 7, 14, and 21. Conclusions We hereby report the association of liver disease with homozygous mutations in the conserved ATP hinge region of exon 18 of the ATP7B gene.