Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

The Wilson disease gene is a putative copper transporting P–type ATPase similar to the Menkes gene

Nature Genetics volume 5, pages 327–337 (1993)Cite this article

A Correction to this article was published on 01 February 1994

Abstract

Wilson disease (WD) is an autosomal recessive disorder of copper transport, resulting in copper accumulation and toxicity to the liver and brain. The gene (WD) has been mapped to chromosome 13 q14.3. On yeast artificial chromosomes from this region we have identified a sequence, similar to that coding for the proposed copper binding regions of the putative ATPase gene (MNK) defective in Menkes disease. We show that this sequence forms part of a P–type ATPase gene (referred to here as Wc1) that is very similar to MNK, with six putative metal binding regions similar to those found in prokaryotic heavy metal transporters. The gene, expressed in liver and kidney, lies within a 300 kb region likely to include the WD locus. Two WD patients were found to be homozygous for a seven base deletion within the coding region of Wc1. Wc1 is proposed as the gene for WD.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Brewer, G.J. & Yuzbasiyan-Gurkan, V. Wilson Disease. Medicine 71, 139–164 (1992).

    Article  CAS  Google Scholar 

  2. Sarkar, B. Transport of Copper. in Metal ions in biological systems, (ed. Sigel, H.) 233–281 (Marcel Dekker, New York, 1981).

    Google Scholar 

  3. Orena, S.J., Goode, C.A. & Linder, M.C. Binding and uptake of copper from ceruloplasmin. Biochem. Biophys. Res. Commun. 139, 822–829 (1986).

    Article  CAS  Google Scholar 

  4. Kagi, J.H.R. & Schaffer, A. Biochemistry of metallothionein. Biochemistry 27, 8509–8515 (1988).

    Article  CAS  Google Scholar 

  5. Danks, D.M. Disorders of copper transport. in: Metabolic Basis of Inherited Disease, (eds Beaudet, A.L., Sly, W.S. & Valle, D.) 1411–1431 (McGraw-Hill, New York, 1989).

    Google Scholar 

  6. Darwish, H.M., Hoke, J.E. & Ettinger, M.J. Kinetics of Cu(II) transport and accumulation by hepatocytes from copper-deficient mice and the brindled mouse model of Menkes disease. J. biol. Chem. 258, 13621–13626 (1983).

    CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Bowcock, A.M. et al. Mapping the Wilson 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 

  9. Bowcock, A.M. et al. Eight closely linked loci place the Wilson disease locus within 13q14-q21. Am. J. hum. Genet. 43, 664–674 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Yuzbasiyan-Gurkan, V., Brewer, G.J., Boerwinkle, E. & Venta, P.J. Linkage of the Wilson disease gene to chromosome 13 in North-American pedigrees. Am. J. hum. Genet. 42, 825–829 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  12. Thomas, G.R., et al. Allelic association and linkage studies in Wilson disease. Hum. molec. Genet. 2, 1404–1405 (1993).

    Google Scholar 

  13. Houwen, R.H.J., Berger, R., Cox, D.W. & Buys, C.H.C.M. Allelic association for Wilson disease-D13S31. J. Hepatol. 16, S15 (1992).

    Google Scholar 

  14. Bull, P.C. et al. Isolation of new probes in the region of the Wilson disease locus, 13q14.2-14.3. Cytogenet. Cell. Genet. 64, 12–17 (1993).

    Article  CAS  Google Scholar 

  15. Bull, P.C. & Cox, D.W. Long range restriction mapping of 13q14.3 focused on the Wilson disease region. Genomics 16, 593–598 (1993).

    Article  CAS  Google Scholar 

  16. Thomas, G.R., Bull, P.C., Roberts, E.A., Walshe, J.R. & Cox, D.W. Haplotype studies in wilson disease. Am. J. hum. Genet. (in the press).

  17. 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  Google Scholar 

  18. 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  Google Scholar 

  19. 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  Google Scholar 

  20. Sass-Kortsak, A. Copper metabolism. Adv. Clin. Chem. 8, 1–67 (1965).

    CAS  PubMed  Google Scholar 

  21. Owen, C.A. Jr. Metabolism of radiocopper (64Cu) in the rat. Am. J. Physiol. 209, 900–904 (1965).

    CAS  PubMed  Google Scholar 

  22. Rommens, J.M. et al. A transcription map of the region containing the Huntington disease gene. Hum. molec. Genet. 2, 901–907 (1993).

    Article  CAS  Google Scholar 

  23. Goldberg, Y.P. et al. Cloning and mapping of the a-adducin gene close to D4S95 and assessment of its relationship to Huntington disease. Hum. molec. Genet. 1, 669–675 (1992).

    Article  CAS  Google Scholar 

  24. Silver, S., Nucifora, G. & Phang, Le.T. Human Menkes X-chromosome disease and the staphylococcal cadmium resistance ATPase: a remarkable similarity in protein sequences. Molec. Microbiol. 10, 7–12 (1993).

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  26. Griffin, H.G., Foster, T.J., Silver, S. & Misra, T.K. Cloning and DNA sequence of the mercuric and organomercurial resistance determinants of plasmid pDU1358. Proc. natn. Acad. Sci. U.S.A. 84, 3112–3116 (1987).

    Article  CAS  Google Scholar 

  27. 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 

  28. Green, N.M. & Stokes, D.L. Structural modelling of P-type ion pumps. Acta Physiol. Scand. 146, 59–68 (1993).

    Google Scholar 

  29. MacLennan, D.H., Clarke, D.M., Loo, T.W. & Skerjanc, I.S. Site-directed mutagenesis of the Ca2+ ATPase of sarcoplasmic reticulum. Acta Physiol. Scand. 146, 141–150 (1992).

    Article  CAS  Google Scholar 

  30. 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 (Correction). Nature Genet. 3, 273 (1993).

    Article  CAS  Google Scholar 

  31. Yarze, J.C., Martin, P., Munoz, S.J. & Friedman, L.S. Wilson Disease: current status. Am. J. Med. 92, 643–654 (1992).

    Article  CAS  Google Scholar 

  32. Sternlieb, I. Perspectives on Wilson Disease. Hepatology 12, 1234–1239 (1990).

    Article  CAS  Google Scholar 

  33. Yang, F., et al. Characterization, mapping, and expression of the human ceruloplasmin gene. Proc. natn. Acad. Sci. U.S.A. 83, 3257–3261 (1986).

    Article  CAS  Google Scholar 

  34. Sato, M. & Gitlin, J.D. Mechanisms of copper incorporation during the biosythesis of human ceruloplasmin. J. biol. Chem. 266, 5128–5134 (1991).

    CAS  PubMed  Google Scholar 

  35. Gitlin, J.D., Schroeder, J.J., Lee-Ambrose, L.M & Cousins, R.J. Mechanisms of ceruloplasmin biosynthesis in normal and copper-deficient rats. Biochem. J. 282, 835–839 (1992).

    Article  CAS  Google Scholar 

  36. O'Halloran, T.V. Transition metals in control of gene expression. Science 261, 715–725 (1993).

    Article  CAS  Google Scholar 

  37. Scherer, S. & Tsui, L-T. Cloning and analysis of large DNA molecules. in Advanced techniques in chromosome research (ed. Adolph, K.W.) 33–72 (Marcel Dekker, New York, 1991).

    Google Scholar 

  38. Triglia, T., Peterson, M.G. & Kemp, D.J. A procedure for in vitro amplification of DNA segments that lie outside the boundaries of known sequences. Nucl. Acids Res. 16, 8186–8180 (1988).

    Article  CAS  Google Scholar 

  39. Sambrook, J., Fritsch, E.F. & Maniatis, T. Molecular cloning, a laboratory manual (Cold Spring Harbor Laboratory Press, New York, 2nd edn 1989).

    Google Scholar 

  40. Orita, M., Suzuki, Y., Sekiya, T. & Hayashi, K. Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics 5, 874–879 (1989).

    Article  CAS  Google Scholar 

  41. White, M.B., Carvalho, M., Derse, D., O'Brien, S.J. & Dean, M. Detecting single base substitutions as heteroduplex polymorphisms. Genomics 12, 301–306 (1992).

    Article  CAS  Google Scholar 

  42. 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 

  43. Kahn, D. et al. Rhizobium melitoli fixGHI sequence predicts involvement of a specific cation pump in symbiotic nitrogen fixation. J. Bacteriol. 171, 929–939 (1989).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Research Institute, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada, M5G 1X8

    Peter C. Bull, Gordon R. Thomas, Johanna M. Rommens, John R. Forbes & Diane Wilson Cox

  2. Department of Molecular and Medical Genetics, University of Toronto, Toronto, Canada

    Gordon R. Thomas, Johanna M. Rommens & Diane Wilson Cox

  3. Department of Paediatrics, University of Toronto, Toronto, Canada

    Diane Wilson Cox

Authors
  1. Peter C. Bull
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gordon R. Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Johanna M. Rommens
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John R. Forbes
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Diane Wilson Cox
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bull, P., Thomas, G., Rommens, J. et al. The Wilson disease gene is a putative copper transporting P–type ATPase similar to the Menkes gene. Nat Genet 5, 327–337 (1993). https://doi.org/10.1038/ng1293-327

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1293-327

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing