IDENTIFICATION AND ANALYSIS OF MUTATIONS IN THE WILSON-DISEASE GENE (ATP7B) - POPULATION FREQUENCIES, GENOTYPE-PHENOTYPE CORRELATION, AND FUNCTIONAL ANALYSES

Wilson disease (WD) is an autosomal recessive disorder characterized b y toxic accumulation of copper in the liver and subsequently in the br ain and other organs. On the basis of sequence homology to known genes , the WD gene (ATP7B) appears to be a copper-transporting P-type ATPas e. A search for ATB7B mutations in WD patients from five population sa mples, including 109 North American patients, revealed 27 distinct mut ations, 18 of which are novel. A composite of published findings shows missense mutations in all exons-except in exons 1-5, which encode the six copper-binding motifs, and in exon 21, which spans the carboxy-te rminus and the poly(A) tail. Over one-half of all WD mutations occur o nly rarely in any population sample. A splice-site mutation in exon 12 accounts for 3% of the WD mutations in our sample and produces an in- frame, 39-bp insertion in mRNA of patients homozygous, but not heteroz ygous, for the mutation. The most common WD mutation (His1069Glu) was represented in similar to 38% of all the WD chromosomes from the North American, Russian, and Swedish samples. In several population cohorts , this mutation deviated from Hardy-Weinberg equilibrium, with an over representation of homozygotes. We did not find a significant correlati on between His1069Glu homozygosity and several clinical indices, inclu ding age of onset, clinical manifestation, ceruloplasmin activity, hep atic copper levels, and the presence of Kayser-Fleischer rings. Finall y, lymphoblast cell lines from individuals homozygous for His1069Glu a nd 4 other mutations all demonstrated significantly decreased copper-s timulated ATPase activity.