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© 1994 Oxford University Press

OTHER

Characterization of the Wilson disease gene encoding a P-type copper transporting ATPase: genomic organization, alternative splicing, and structure/function predictions

Konstantin Petrukhin, Svetiana Lutsenko1,+, Igor Chernov, Barbara M. Ross, Jack H. Kaplan1,+ and T.Conrad Gilliam*

Departments of Genetics and Development and Psychiatry, College of Physicians and Surgeons at Columbia University, and New York State Psychiatric Institute 722 West 168th Street, New York, NY 10032 1Department of Physiology, University of Pennsylvania 3700 Hamilton WalkPhiladelphia, PA 19104, USA

*To whom correspondence should be addressed

+Present address: Department of Biochemistry and Molecular Biology, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 97201-3098, USA

Received May 25, 1994; Revised July 8, 1994; Accepted July 8, 1994

Wilson disease is an autosomal recessive disorder of copper transport. Disease symptoms develop from the toxic build-up of copper primarily in the liver, and subsequently in the brain, kidney, cornea and other tissues. A candidate gene for WD (ATP7B) has recently been identified based upon apparent disease-specific mutations and a striking amino acid homology to the gene (ATP7A) responsible for another human copper transport disorder, X-linked Menkes disease (MNK). The cloning of WD and MNK genes provides the first opportunity to study copper homeostasis in humans. A preliminary analysis of the WD gene is presented which includes: Isolation and characterization of the 5'-end of the gene; construction of a genomic restriction map; Identification of all 21 exon/intron boundaries; characterization of extensive alternative splicing in brain; prediction of structure/function features of the WD and MNK proteins which are unique to the subset of heavy metal-transporting P-type ATPases; and comparative analysis of the six metal-binding domains. The analysis indicates that WD and MNK proteins belong to a subset of transporting ATPases with several unique features presumably reflecting their specific regulation and function. It appears that the mechanism of alternative splicing serves to regulate the amount of functional WD protein produced in brain, kidney, placenta, and possibly in liver.


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