title: Null mutation of the murine ATP7B (Wilson disease) gene results in intracellular copper accumulation and late-onset hepatic nodular transformation.
abstract: The Atp7b protein is a copper-transporting ATPase expressed predominantly in the liver and to a lesser extent in most other tissues. Mutations in the ATP7B gene lead to Wilson disease, a copper toxicity disorder characterized by dramatic build-up of intracellular hepatic copper with subsequent hepatic and neuro-logical abnormalities. Using homologous recombination to disrupt the normal translation of ATP7B, we have generated a strain of mice that are homozygous mutants (null) for the Wilson disease gene. The ATP7B null mice display a gradual accumulation of hepatic copper that increases to a level 60-fold greater than normal by 5 months of age. An increase in copper concentration was also observed in the kidney, brain, placenta and lactating mammary glands of homo-zygous mutants, although milk from the mutant glands was copper deficient. Morphological abnormalities resembling cirrhosis developed in the majority of the livers from homozygous mutants older than 7 months of age. Progeny of the homozygous mutant females demonstrated neurological abnormalities and growth retardation characteristic of copper deficiency. Copper concentration in the livers of the newborn homozygous null mutants was decreased dramatically. In summary, inactivation of the murine ATP7B gene produces a form of cirrhotic liver disease that resembles Wilson disease in humans and the 'toxic milk' phenotype in the mouse.
authors.affiliation: Department of Genetics and Development, Columbia University, The NationalCenter for the Studyof Wilson's Disease and St. Luke's Roosevelt Ho spital, New York, NY 10032, USA.
authors.forename: O I
authors.initials: OI
authors.lastname: Buiakova
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.forename: S
authors.initials: S
authors.lastname: Lutsenko
authors.forename: S
authors.initials: S
authors.lastname: Zeitlin
authors.forename: K
authors.initials: K
authors.lastname: Das
authors.forename: S
authors.initials: S
authors.lastname: Das
authors.forename: B M
authors.initials: BM
authors.lastname: Ross
authors.forename: C
authors.initials: C
authors.lastname: Mekios
authors.forename: I H
authors.initials: IH
authors.lastname: Scheinberg
authors.forename: T C
authors.initials: TC
authors.lastname: Gilliam
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D002352:Carrier Proteins / Q000235:genetics*; D027682:Cation Transport Proteins; D003300:Copper / Q000378:metabolism*; D000073840:Copper-Transporting ATPases; D005355:Fibrosis / Q000235:genetics; D006527:Hepatolenticular Degeneration / Q000235:genetics*; D006720:Homozygote; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010641:Phenotype
chemical_list: D002352:Carrier Proteins; D027682:Cation Transport Proteins; D003300:Copper; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases