Haplotype and Mutation Analysis in Japanese Patients with Wilson Disease

• Published in: American journal of human genetics Vol. 60; no. 6; pp. 1423 - 1429
• Main Authors: Nanji, Manoj S., Van Nguyen, T.T., Kawasoe, Jean H., Inui, Koji, Endo, Fumio, Nakajima, Takashi, Anezaki, Toshiharu, Cox, Diane W.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.06.1997; University of Chicago Press
• Subjects: Adenosine Triphosphatases - genetics; Base Sequence; Biological and medical sciences; Carrier Proteins - genetics; Cation Transport Proteins; Copper-transporting ATPases; DNA - blood; DNA Mutational Analysis; DNA Primers; DNA Transposable Elements; Exons; Genetic Markers; Haplotypes; Hepatolenticular Degeneration - blood; Hepatolenticular Degeneration - genetics; Humans; Japan; Medical sciences; Metabolic diseases; Metals (hemochromatosis...); Molecular Sequence Data; Mutation; Other metabolic disorders; Point Mutation; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Repetitive Sequences, Nucleic Acid; Sequence Deletion; Asia; Japan; Genetic mapping; Human; Nervous system diseases; Genetic inheritance; Transcription; Wilson disease; Family study; Hot spot; Metabolic diseases; Enzymopathy; Genetic disease; Starting; Digestive diseases; Genetics; Mutation; Haplotype
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/515459

Wilson disease (WD), an autosomal recessive disorder of copper transport, is characterized by impaired biliary excretion and by impaired incorporation of copper into cerulo-plasmin. 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 predicted to be a copper-transporting P-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 identification of at least 40 mutations. In addition, haplotype analysis using three di-nucleotide-repeat markers, D13S314, D13S301, and D13S316, has been a useful indicator of specific mutations. We have determined haplotypes for the patients and their parents and sibs, in 21 unrelated WD families from Japan. Twenty-eight different haplotypes were observed on 42 WD chromosomes. In all the patients, the ATP7B coding sequence, including the intron-exon boundaries, was screened for mutations, by SSCP, 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 coding region. The mutations reported in previous studies are 2299insC and Arg778Leu. Two patients were shown to have the 2299insC mutation, which has occurred in many different haplotypes in several populations, indicating a mutation hot spot. Primer-extension analysis of ATP7B mRNA has revealed multiple transcription start sites. Four of the novel mutations (three 1-bp changes and one 5-bp deletion) occur in the 5′ UTR and may result in altered expression of the WD gene.