HAPLOTYPE AND MUTATION ANALYSIS IN JAPANESE PATIENTS WITH WILSON-DISEASE

Citation
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
Citations number
20
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Genetics & Heredity
ISSN journal
0002-9297
Volume
60
Issue
6
Year of publication
1997
Pages
1423 - 1429
Database
ISI
SICI code
0002-9297(1997)60:6<1423:HAMAIJ>2.0.ZU;2-F
Abstract
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.