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The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene

Nature Genetics volume 5, pages 344–350 (1993)Cite this article

Abstract

Wilson disease (WD) is an autosomal recessive disorder characterized by the toxic accumulation of copper in a number of organs, particularly the liver and brain. As shown in the accompanying paper, linkage disequilibrium & haplotype analysis confirmed the disease locus to a single marker interval at 13q14.3. Here we describe a partial cDNA clone (pWD) which maps to this region and shows a particular 76% amino acid homology to the Menkes disease gene, Mc1. The predicted functional properties of the pWD gene together with its strong homology to Mc1, genetic mapping data and identification of four independent disease–specific mutations, provide convincing evidence that pWD is the Wilson disease gene.

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References

  1. Scheinberg, I.H. & Sternlieb, I. Wilon's Disease. Volume XXIII in Major Problems in Internal Medicine. Vol, XXII (ed. Lloyd H. Smith Jr.) (Saunders, Philadelphia, 1984).

    Google Scholar 

  2. Wilson, S.A.K. Progressive lenticular degeneration: A familial nervous disease associated with cirrhosis of the liver. Brain 34, 295–509 (1912).

    Article  Google Scholar 

  3. Frydman, M. et. al. Assignment of the gene for Wilson disease to chromosome 13: Linkage to the esterase D locus. Proc. natn. Acad. Sci. U.S.A. 82, 1819–1821 (1985).

    Article  CAS  Google Scholar 

  4. Bonne'-Tamir, B., Farrer, L.A., Frydman, M. & Kannaane, L.H. Evidence for linkage between Wilsons disease and esterase D in three kindreds: detection of linkage for an autosomal recessive disorder in the family study method. Genet. Epidemiol. 3, 201–209 (1986).

    Article  CAS  Google Scholar 

  5. Bowcock, A.M. et al. Mapping the Wilson's disease locus to a cluster of linked polymorphic markers on chromosome 13. Am. J. hum. Genet. 41, 27–35 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Farrer, L.A. et al. Predictive testing for Wilsons disease using tightly linked and flanking DNA markers. Neurology 41, 992–999 (1991).

    Article  CAS  PubMed  Google Scholar 

  7. Bowcock, A.M., Farrer, L.A., Herber, J.M., Bale, A.E. & Cavalli-Sforza, L.L. A contiguous linkage map of chromosome 13q with 39 distinct loci separated on average by 5.1 centimorgans. Genomics 11, 517–529 (1991).

    Article  CAS  PubMed  Google Scholar 

  8. Thomas, G.R. et al. Allelic association and linkage studies in Wilson disease. Hum. molec. Genet. 2, 1401–1405 (1993).

    Article  CAS  PubMed  Google Scholar 

  9. Stewart, E.A. et al. Polymorphic microsatellites and Wilson Disease (WD). Am. J. hum. Genet. 53, 864–873 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Petrukhin, K. et al. Mapping, cloning and genetic characterization of the regions containing the Wilson disease locus. Nature Genet. 5, 338–343 (1993).

    Article  CAS  PubMed  Google Scholar 

  11. Bush, A.I., Pettingell, W., Wasco, W., & Tanzi, R.E. Zinc-induced precipitation of βA4 is prevented by copper. Soc. Neurosci. Abs. 19, 19 (1993).

    Google Scholar 

  12. Glenner, G.G. & Wong, C.W. Alzheimer's disease: Initial report of the purification and characterization of a novel cerebral vascular amyloid protein. Biochem. biophy. Res. Commun. 120, 885–890 (1984).

    Article  CAS  Google Scholar 

  13. Vulpe, C., Levinson, B., Whitney, S., Packman, S. & Gitschier, J. Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase. Nature Genet. 3, 7–13 (1993).

    Article  CAS  PubMed  Google Scholar 

  14. Chelly, J. et al. Isolation of a candidate gene for Menkes disease that encodes a potential heavy metal binding protein. Nature Genet. 3, 14–19 (1993).

    Article  CAS  PubMed  Google Scholar 

  15. Mercer, J.F.B. et al. Isolation of a partial candidate gene for Menkes disease by positional cloning. Nature Genet. 3, 20–25 (1993).

    Article  CAS  PubMed  Google Scholar 

  16. Adams, M.D. et al. Rapid cDNA sequencing (expressed sequence tags) from a directionally cloned human infant brain cDNA library. Nature Genet. 4, 373–380 (1993).

    Article  CAS  PubMed  Google Scholar 

  17. Soares, M.B. Construction of directionally cloned cDNA libraries in phagemid vectors. in Automated DNA sequencing and analysis techniques. (ed. J.C. Ventor) (Academic Press, London, in the press).

  18. Oedermatt, A., Suter, H., Kraps, R. & Solioz, M. Primary structure of two P-type ATPases involved in copper homeostasis in Enterococcus hirae. J. biol. Chem. 268, 12775–12779 (1993).

    Google Scholar 

  19. Ivy, D.M. et al. The cad C gene product of Alkalophilic Bacillus firmus OF4 partially restores Na+ resistance to an Escherichia coli strain lacking an Na+/H+ antiporter (NhaA). J. Bacteriol. 174, 4878–4884 (1992).

    Article  Google Scholar 

  20. Silver, S. & Walderhaug, M. Gene regulation of plasmid and chromosomal determined inorganic ion transport in bacteria. Microbiol. Rev. 56, 195–222 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Silver, S., Nucifora, G., Chu, L. & Misra, T.K. Bacterial resistance ATPases: primary pumps for exporting toxic cations and anions. Trends biochem. Sci. 14, 76–80 (1989).

    Article  CAS  PubMed  Google Scholar 

  22. Devereau, J., Haeberli, P. & Smithies, O. A comprehensive set of sequence analysis programs for the VAX. Nucl. Acid Res. 12, 387–395 (1984).

    Article  Google Scholar 

  23. Nucifora, G., Chu, L., Misra, T.K. & Silver, S. Cadmium resistance from Staphylococcus aureus plasmid pl258 cadA gene results from a cadmium efflux ATPase. Proc. natn. Acad. Sci. U.S.A. 86, 3544–3548 (1989).

    Article  CAS  Google Scholar 

  24. Vilsen, B., Andersen, J.P., Clarke, D.M. & MacLennan, D.H., Functional consequences of proline mutations in the cytoplasmic and transmembrane sectors of the Ca2+-ATPase of sarcoplasmic reticulum. J. biol. Chem. 264, 21024–21030 (1989).

    CAS  PubMed  Google Scholar 

  25. Eisenberg, D., Weiss, R.M. & Terwilliger, T.C. The hydrophobic moment detects periodicity in protein hydrophobicity. Proc. natn. Acad. Sci. U.S.A. 81, 140–144 (1984).

    Article  CAS  Google Scholar 

  26. Branden, C. & Tooze, J. Introduction to protein structure (Garland Publishing, New York 1991).

    Google Scholar 

  27. Menkes, J.H., Alter, M., Steigleder, G.K., Weakley, D.R. & Sung, J.H. A sex-linked recessive disorder with retardation of growth, peculiar hair and focal cerebral and cerebellar degeneration. Pediatrics 29, 764–779 (1962).

    CAS  PubMed  Google Scholar 

  28. Gibbs, K. & Walshe, J.M. A study of the caeruloplasmin concentrations found in 75 patients with Wilson's disease, their kinships and various control groups. Quart. J. Med. 48, 447 (1979).

    CAS  PubMed  Google Scholar 

  29. Sass-Kortsak, A. & Bearn, A.G. in The Metabolic Basis of Inherited Disease 4th ed (ed. Stanbury J.B. et al.) 1098–1126 (McGraw-Hill, New York, 1978).

    Google Scholar 

  30. Chomczunsky, P. & Sacchi, N. Single-step method of RNA isolation by acid guanidinum thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162, 156–159 (1987).

    Article  Google Scholar 

  31. Maniatis, T., Fritsch, E.F. & Sambrook, J. Molecular Cloning. A Laboratory Manual. (Cold Spring Harbor Laboratories, New York, 1989).

    Google Scholar 

  32. Altschul, S.F., Gish, W., Miller, W., Myers, E.W. & Lipman, D.J. Basic Local Alignment Search Tool. J. molec. Biol. 215, 403–410 (1990).

    Article  CAS  PubMed  Google Scholar 

  33. Kyte, J. & Doolittle, R.F. A simple method for displaying the hydropathic character of a protein. J. molec. Biol. 157, 105–132 (1982).

    Article  CAS  PubMed  Google Scholar 

  34. Pellequer, J-L., Westhof, L. & Van Regenmortel, M.H.V. Correlation between the location of antigenic sites and the prediction of turns in proteins. Immunol. Lett. 36, 83–100 (1993).

    Article  CAS  PubMed  Google Scholar 

  35. Cornette, J.L. et al. Hydrophobicity scales and computational techniques for detecting amphipathic structures in proteins. J. molec. Biol. 195, 659–685 (1987).

    Article  CAS  PubMed  Google Scholar 

  36. Chou, P.Y. & Fasman, G.D. Prediction of protein conformation. Biochem. 13, 222–245 (1974).

    Article  CAS  Google Scholar 

  37. Garnier, J., Osguthorpe, D.J. & Robson, B. Analysis of the accuracy and implications of simple methods for predicting the secondary structure of globular proteins. J. molec. Biol. 120, 97–120 (1978).

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Neurology Department, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, 02114, USA

    R.E. Tanzi, W. Wasco, D.M. Romano, J. Peppercorn, A.I. Bush & J.F. Gusella

  2. Department of Psychiatry, New York, New York, 10032, USA

    K. Petrukhin, I. Chernov, B. Ross, L.M. Brzustowicz, M. Devoto, G.K. Penchaszadeh, M.B. Soares & T.C. Gilliam

  3. Department of New York State Psychiatric Institute, New York, New York, 10032, USA

    K. Petrukhin, I. Chernov, B. Ross, L.M. Brzustowicz, M. Devoto, G.K. Penchaszadeh, M.B. Soares & T.C. Gilliam

  4. Department of Biochemistry and Molecular Biophysics, New York, New York, 10032, USA

    J.L. Pellequer, B. Honig & I.S. Edelman

  5. Pediatric Clinic, University of Catania, Italy

    E. Parano & L. Pavone

  6. Department of Medicine, Columbia University, New York, New York, 10032, USA

    I. Sternlieb & I.H. Scheinberg

  7. The National Center for the Study of Wilson's Disease, New York, New York, 10019, USA

    I. Sternlieb & I.H. Scheinberg

  8. St. Luke's Roosevelt Hospital, New York, New York, 10019, USA

    I. Sternlieb & I.H. Scheinberg

  9. Instituto di Ricerca sulle Talassemie ed Anemie Mediterranee CNR, Cagliari, Italy

    M. Pirastu

  10. Research Center of Medical Genetics, Moscow, Russia

    O. Evgrafov

  11. Department of Center for Reproductive Sciences, New York, New York, 10032, USA

    I.S. Edelman

  12. Department of Genetics and Development, New York, New York, 10032, USA

    T.C. Gilliam

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  1. R.E. Tanzi
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Tanzi, R., Petrukhin, K., Chernov, I. et al. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet 5, 344–350 (1993). https://doi.org/10.1038/ng1293-344

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