Ms. Nanji et al., HAPLOTYPE AND MUTATION ANALYSIS IN JAPANESE PATIENTS WITH WILSON-DISEASE, American journal of human genetics, 60(6), 1997, pp. 1423-1429
Wilson disease (WD), an autosomal recessive disorder of copper transpo
rt, is characterized by impaired biliary excretion and by impaired inc
orporation of copper into ceruloplasmin. Toxic accumulation of copper
causes tissue damage, primarily in the liver, brain, and kidneys. The
gene for WD (ATP7B) has been cloned, and the protein product is predic
ted to be a copper-transporting beta-type ATPase with high amino acid
identity with that for Menkes disease, an X-linked disorder of copper
transport. Mutation screening in WD patients has led to the identifica
tion of at least 40 mutations. In addition, haplotype analysis using t
hree dinucleotide-regeat markers, D13S314, D13S301, and D13S316, has b
een a useful indicator of specific mutations. We have determined haplo
types for the patients and their parents and sibs, in 21 unrelated WD
families from Japan. Twenty-eight different haplotypes were observed o
n 42 WD chromosomes. In all the patients, the ATP7B coding sequence, i
ncluding the intron-exon boundaries, was screened for mutations, by SS
CP, followed by direct-sequence analysis of the shifted fragments. We
identified 13 mutations, of which 11 mutations are novel, including 7
mutations-1 insertion, 4 deletions, and 2 missense mutations-in the co
ding region. The mutations reported in previous studies are 2299insC a
nd Arg778Leu. Two patients were shown to have the 2239insC mutation, w
hich has occurred in many different haplotypes in several populations,
indicating a mutation hot spot. Primer-extension analysis of ATP7B mR
NA has revealed multiple transcription start sites. Four of the novel
mutations (three 1-bp changes and one 5-bp deletion) occur in the 5' U
TR and may result in altered expression of the WD gene.