title: Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation, and functional analyses.
abstract: Wilson disease (WD) is an autosomal recessive disorder characterized by toxic accumulation of copper in the liver and subsequently in the brain and other organs. On the basis of sequence homology to known genes, the WD gene (ATP7B) appears to be a copper-transporting P-type ATPase. A search for ATP7B mutations in WD patients from five population samples, including 109 North American patients, revealed 27 distinct mutations, 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-terminus and the poly(A) tail. Over one-half of all WD mutations occur only 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 heterozygous, for the mutation. The most common WD mutation (His1069Glu) was represented in approximately 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 overrepresentation of homozygotes. We did not find a significant correlation between His1069Glu homozygosity and several clinical indices, including age of onset, clinical manifestation, ceruloplasmin activity, hepatic copper levels, and the presence of Kayser-Fleischer rings. Finally, lymphoblast cell lines from individuals homozygous for His1069Glu and 4 other mutations all demonstrated significantly decreased copper-stimulated ATPase activity.
authors.affiliation: Department of Genetics and Development, Columbia University, New York, NY 10032, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Shah
authors.forename: I
authors.initials: I
authors.lastname: Chernov
authors.forename: H T
authors.initials: HT
authors.lastname: Zhang
authors.forename: B M
authors.initials: BM
authors.lastname: Ross
authors.forename: K
authors.initials: K
authors.lastname: Das
authors.forename: S
authors.initials: S
authors.lastname: Lutsenko
authors.forename: E
authors.initials: E
authors.lastname: Parano
authors.forename: L
authors.initials: L
authors.lastname: Pavone
authors.forename: O
authors.initials: O
authors.lastname: Evgrafov
authors.forename: I A
authors.initials: IA
authors.lastname: Ivanova-Smolenskaya
authors.forename: G
authors.initials: G
authors.lastname: Annerén
authors.forename: K
authors.initials: K
authors.lastname: Westermark
authors.forename: F H
authors.initials: FH
authors.lastname: Urrutia
authors.forename: G K
authors.initials: GK
authors.lastname: Penchaszadeh
authors.forename: I
authors.initials: I
authors.lastname: Sternlieb
authors.forename: I H
authors.initials: IH
authors.lastname: Scheinberg
authors.forename: T C
authors.initials: TC
authors.lastname: Gilliam
authors.forename: K
authors.initials: K
authors.lastname: Petrukhin
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000328:Adult; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D027682:Cation Transport Proteins; D002648:Child; D000073840:Copper-Transporting ATPases; D004252:DNA Mutational Analysis; D016368:Frameshift Mutation; D005787:Gene Frequency; D005796:Genes; D005838:Genotype; D006239:Haplotypes; D006527:Hepatolenticular Degeneration / Q000201:enzymology / Q000208:ethnology / Q000235:genetics*; D006801:Humans; D017720:Molecular Epidemiology; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009154:Mutation; D009693:Nucleic Acid Hybridization; D010641:Phenotype; D017354:Point Mutation; D012150:Polymorphism, Restriction Fragment Length; D018807:Polymorphism, Single-Stranded Conformational; D012326:RNA Splicing; D017384:Sequence Deletion
chemical_list: D002352:Carrier Proteins; D027682:Cation Transport Proteins; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases