Human Molecular Genetics, 1999, Vol. 8, No. 9 1665-1671
© 1999 Oxford University Press
Null mutation of the murine ATP7B (Wilson disease) gene results in intracellular copper accumulation and late-onset hepatic nodular transformation
1Department of Genetics and Development, 2Department of Psychiatry, 3Department of Pathology and 4Columbia Genome Center, Columbia University, 5The National Center for the Study of Wilson’s Disease and St Luke’s Roosevelt Hospital, New York, NY 10032, USA and 6Department of Biochemistry and Molecular Biology, School of Medicine, Oregon Health Science University, Portland, OR 97201, USA
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 neurological 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 homozygous 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.
+ To whom correspondence should be addressed at: Columbia Genome Center, 1150 St Nicholas Avenue, 5th floor, New York, NY 10032, USA. Tel: +1 212 304 7984; Fax: +1 212 304 5515; Email: tcg1{at}columbia.edu
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