Gordon R. Thomas

The Wilson disease gene is a putative copper transporting P–type ATPase similar to the Menkes gene

Wilson disease (WD) is an autosomal recessive disorder of copper transport, resulting in copper accumulation and toxicity to the liver and brain. The gene (WD) has been mapped to chromosome 13 q14.3. On yeast artificial chromosomes from this region we have identified a sequence, similar to that coding for the proposed copper binding regions of the putative ATPase gene (MNK) defective in Menkes disease. We show that this sequence forms part of a P–type ATPase gene (referred to here as Wc1) that is very similar to MNK, with six putative metal binding regions similar to those found in prokaryotic heavy metal transporters. The gene, expressed in liver and kidney, lies within a 300 kb region likely to include the WD locus. Two WD patients were found to be homozygous for a seven base deletion within the coding region of Wc1. Wc1 is proposed as the gene for WD.

DNA markers for the diagnosis of Wilson disease

Wilson disease is an autosomal recessive disorder of copper transport for which the basic defect is unknown. Laboratory diagnosis of Wilson disease is usually made by measuring serum ceruloplasmin concentration, urinary copper excretion, and liver copper concentration. However, discrimination between heterozygotes and patients is sometimes difficult. The gene for Wilson disease has been assigned to chromosome-13 at q14-q21. In this study, 10 markers from the 13q14-13q21 region were investigated in 12 families with a well-established diagnosis, to confirm reported linkage results. Markers from the same region were tested in two additional families, in which a sib of each index case had unclear results with conventional biochemical assays. The linkage results in this study are similar to those of Middle Eastern families, and support the hypothesis of a single disease locus. In the two families studied for diagnostic purposes, the status of 2 presymptomatic sibs was established as affected and 1 as unaffected. This study therefore shows that DNA markers can be used to discriminate between presymptomatic patients and non-affected individuals when biochemical results are equivocal, as long as an index case with Wilson disease of known status is available and markers are informative.