Wilson disease (WD) is an autosomal recessive defect of copper transport, with impairment of biliary copper excretion and of incorporation of copper into ceruloplasmin. There is considerable variability in presenting symptoms and age of onset. We have cloned the gene for WD (ATP7B) and predicted the product to be a copper transporting P-type ATPase, similar to that for Menkes disease, an X-linked disorder of copper transport.
We have identified more than 25 mutations in the gene (Nat. Genetics 9: 210, 1995). We analyzed the mutations in 67 unrelated patients from Canada and Great Britain, with onset of symptoms less than 18 years of age, using SSCP plus specific mutation analyses. The ethnic origins of the patients were European (52), Indian and Pakistani (9), Oriental (5). Closely-linked flanking, highly polymorphic markers (D13S314-D13S301-D13S316) were determined for patients and their parents. One or both mutations were identified in 41 patients (61%). 21 different mutations were identified. Almost all patients carried 2 different mutations, except for those of Indian or Pakistani origin, where 6 of 9 patients were homozygous for one mutation. In 12 patients from 3 to 9 yrs, mutations could be predicted to destroy gene function. The His1069Gln mutation, the most common mutation in European populations, was rare in patients with an early onset: 3-9 yrs 4%, 10-14 yrs 18%, 15-18 yrs19%. The only other mutations with a frequency greater than 3% were a mutation in the ATP binding domain, Gly1266Lys, at 5%. and mutation in transmembrane domain 4, Arg778Leu, at 3.7% overall, found only in Oriental patients.
