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 mottled gene is the mouse homologue of the Menkes disease gene

Nature Genetics volume 6, pages 369–373 (1994)Cite this article

Abstract

The mottled mouse has been proposed as an animal model for Menkes disease, an X–linked disorder of copper transport. The recent isolation of a copper–transporting ATPase gene responsible for Menkes disease has allowed us to test this hypothesis. Here we report the isolation and sequence of the mouse homologue of this gene. We show that two mottled (Mo) alleles, dappled (Modp) and blotchy (Mobio), have abnormalities in the murine mRNA and that Modp has a partial gene deletion. These studies prove that the mottled mouse is the murine model for Menkes disease, providing the basis for future biochemical and therapeutic studies.

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. Fraser, A.S., Sobey, S. & Spicer, C.C. Mottled, a sex-modified lethal in the house mouse. J. Genet. 51, 217–221 (1953).

    Article  Google Scholar 

  2. Lyon, M.F. Action in the X-chromosome of the Mouse (Mus musculus L). Nature 190, 372–373 (1961).

    Article  CAS  PubMed  Google Scholar 

  3. Miller, J. in X-linked traits: A Catalogue of Loci in Nonhuman Mammals 115–125 (Cambridge University Press, Cambridge, 1990).

    Book  Google Scholar 

  4. Hunt, D.M. Primary defect in copper transport underlies mottled mutants in the mouse. Nature 249, 852–654 (1974).

    Article  CAS  PubMed  Google Scholar 

  5. 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  PubMed  Google Scholar 

  6. Packman, S. Regulation of copper metabolism in the mottled mouse. Arch. Dermatol. 123, 1545–1547 (1987).

    Article  CAS  PubMed  Google Scholar 

  7. Sayed, A.K., Edwards, J.A. & Bannerman, R.M. Copper metabolism of cultured fibroblasts from the brindled mouse (gene symbol Mobr). Proc. Soc. Exp. Biol. Med. 186, 153–156 (1981).

    Article  Google Scholar 

  8. Phillips, M., Camakaris, J. & Danks, D.M. A comparison of phehotype and copper distribution in biotchy and brindled mutant mice and in nutritionally copper deficient controls. Biol. Trace Elem. Res. 29, 11–29 (1991).

    Article  CAS  PubMed  Google Scholar 

  9. Hunt, D.M. Catecholamine biosynthesis and the activity of a number of copper-dependent enzymes in the copper deficient mottled mouse mutants. Comp. Biochem. Physiol. 57, 79–83 (1977).

    CAS  Google Scholar 

  10. Hunt, D.M. & Johnson, D.R. An inherited deficiency in noradrenaline biosynthesis in the brindled mouse. J. Neurochem. 19, 2811–9 (1972).

    Article  CAS  PubMed  Google Scholar 

  11. Rezek, D.L. & Moore, C.L. Depletion of brain mitochondria cytochrome oxidase in the mottled mouse mutant. Exp. Neurol. 91, 640–645 (1986).

    Article  CAS  PubMed  Google Scholar 

  12. Rowe, D.W., McGoodwin, E.B., Martin, G.R. & Grahn, D. Decreased lysyl oxidase activity in the aneurysm-prone, mottled mouse. J. biol. Chem. 252, 939–942 (1977).

    CAS  PubMed  Google Scholar 

  13. Starcher, B.C., Madaras, J.A. & Tepper, A.S. Lysyl oxidase deficiency in lung and fibroblasts from mice with hereditary emphysema. Biochem. Biophys. Res. Common. 78, 706–712 (1977).

    Article  CAS  Google Scholar 

  14. Danks, D.M. in The Metabolic Basis of Inherited Disease (eds Scrives, C. et al.) 1411–1432 (McGraw-Hill, New York, 1989).

    Google Scholar 

  15. Herd, S.M., Camakaris, J., Christofferson, R., Wookey, P. & Danks, D.M. Uptake and efflux of copper-64 in Menkes'-disease and normal continuous lymphoid cell lines. Biochem. J. 247, 341–347 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Horn, N. Copper incorporation studies on cultured cells for prenatal diagnosis of Menkes' disease. Lancet 1, 1156–1158 (1976).

    Article  CAS  PubMed  Google Scholar 

  17. Brockdorff, N. et al. High-density molecular map of the central span of the mouse X chromosome. Genomics 10, 17–22 (1991).

    Article  CAS  PubMed  Google Scholar 

  18. Tonnesen, T., Petterson, A., Kruse, T.A., Gerdes, A.M. & Horn, N. Multipoint linkage analysis in Menkes disease. Am. J. hum. Genet. 50, 1012–1017 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Danks, D.M. Steely hair, mottled mice and copper metabolism. New Engl. J. Med. 293, 1147–1149 (1975).

    Article  CAS  PubMed  Google Scholar 

  20. 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 

  21. Mercer, J.F. 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 

  22. 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 

  23. Inesi, G. & Kirtley, M.R. Structural features of cation transport ATPases. J. Bioenerg. Biomem. 24, 271–283 (1992).

    CAS  Google Scholar 

  24. 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 

  25. Silver, S., Nucifora, G. & Phung, L.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 

  26. 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 

  27. Turner, Z. et al. Characterization of a 1.0 Mb YAC contig spanning two chromosome breakpoints related to Menkes disease. Hum. molec. Genet. 1, 483–489 (1992).

    Article  Google Scholar 

  28. Royce, P.M., Camakaris, J. & Danks, D.M. Reduced lysyl oxidase activity in skin fibroblasts from patients with Menkes' syndrome. Biochem. J. 192, 579–586 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Holstein, T.J., Fung, R.Q., Quevedo, W.J. & Bieniekl, T.C. Effect of altered copper metabolism Induced by mottled alleles and diet on mouse tyrosinase. Proc. Soc. Exp. Biol. Med. 162, 264–268 (1979).

    Article  CAS  PubMed  Google Scholar 

  30. Lorette, G. et al. Menkes syndrome. An unusual pigmentation anomaly in a mother and three sisters. Ann. Pediatr. 39, 453–456 (1992).

    CAS  Google Scholar 

  31. Hirano, A., Liena, J.F., French, J.H. & Ghatak, N.R. Fine structure of the cerebellar cortex in Menkes Kinky-hair dlsease. X-chromosome-llnked copper malabsorption. Arch. Neurol. 34, 52–56 (1977).

    Article  CAS  PubMed  Google Scholar 

  32. Horn, N., Tonnesen, T. & Turner, Z.N. Menkes disease an X-linked neurological disorder of the copper. Brain Pathol. 2, 351–362 (1992).

    Article  CAS  PubMed  Google Scholar 

  33. Purpura, D.P., Hirano, A. & French, J.H. Purkinje cells in X-chromosome linked copper malabsorption: a Golgi study. Brain Res. 117, 125–129 (1976).

    Article  CAS  PubMed  Google Scholar 

  34. Danks, D.M. The mild form of Menkes disease: progress report on the original case. Am. J. med. Genet. 30, 859–864 (1988).

    Article  CAS  PubMed  Google Scholar 

  35. Gerdes, A.M. et al. Variability in clinical expression of Menkes syndrome. Eur. J. Ped. 148, 132–135 (1988).

    Article  CAS  Google Scholar 

  36. Sander, C., Niederhoff, H. & Horn, N. Life-span and Menkes kinky hair syndrome: report of a 13-year course of this disease. Clin. Genet. 33, 228–233 (1988).

    Article  CAS  PubMed  Google Scholar 

  37. Levinson, B. et al. Are X-linked cutis laxa and Menkes disease allelic? Nature Genet. 3, 6 (1993).

    Article  CAS  PubMed  Google Scholar 

  38. Kuivaniemi, H., Peltonen, L., Palotie, A., Kaitila, I. & Kivirikko, K.I. Abnormal copper metabolism and deficient lysyl oxidase activity inaheritable connective tissue disorder. J. clin. Invest. 69, 730–3 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Menkes, J.H. Kinky hair disease: twenty five years later. Brain Dev. 10, 77–79 (1988).

    Article  CAS  PubMed  Google Scholar 

  40. Nagara, H., Yajima, K. & Suzuki, K. The effect of copper supplementation on the brindled mouse: a clinico-pathological study. J. Neuropathol. Exp. Neurol. 40, 428–446 (1981).

    Article  CAS  PubMed  Google Scholar 

  41. Shiraishl, N., Aono, K. & Taguchi, T. Copper metabolism in the macular mutant mouse: an animal model of Menkes's kinky-hair disease. Biol. Neo. 54, 173–180 (1988).

    Article  Google Scholar 

  42. Fujii, T., Ito, M., Tsuda, H. & Mikawa, H. Biochemical study on the critical period for treatment of the mottled brindled mouse. J. Neurochem. 55, 885–889 (1990).

    Article  CAS  PubMed  Google Scholar 

  43. Mann, J.R., Camakaris, J., Danks, D.M. & Walliczek, E.G. Copper metabolism in mottled mouse mutants: copper therapy of brindled (Mobr) mice. Biochem. J. 180, 605–612 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Tanaka, K. et al. Effects of chelators on copper therapy of macular mouse, a model animal of Menkes' kinky disease. Res. Commun. Chem. Pathol. Pharmacol. 69, 217–227 (1990).

    CAS  PubMed  Google Scholar 

  45. Danks, D.M. & Camakaris, J. Mutations affecting trace elements in humans and animals. Adv. hum. Genet. 13, 149–216 (1983).

    Article  CAS  PubMed  Google Scholar 

  46. Deng, H.X. et al. Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase. Science 261, 1047–1051 (1993).

    Article  CAS  PubMed  Google Scholar 

  47. DiMauro, S. et al. Cytochrome c oxidase deficiency. Pediatr. Res. 28, 536–541 (1990).

    Article  CAS  PubMed  Google Scholar 

  48. Getting, W.S. & King, R.A. Analysis of mutations in the copper B binding region associated with type I (tyrosinase-related) oculocutaneous albinism. Pigment Cell Res. 274–278 (1992).

  49. Packman, S., Palmiter, R.D., Karin, M. & O'Toole, C. Metallothionein messenger RNA regulation in the mottled mouse and Menkes kinky hair syndrome. J. clin. Invest. 79, 1338–1342 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hoffman, C.S. & Winston, F. A ten-minute DNA preparation from yeast efficiently releases autonomous plasmids for transformation of Escherichia coli. Gene 57, 267–272 (1987).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Barbara Levinson and Christopher Vulpe: The first two authors contributed equally

Authors and Affiliations

  1. Departments of Medicine, University of California, San Francisco, California, 94143-0724, USA

    Barbara Levinson, Bruce Elder & Jane Gitschier

  2. Department of Biochemistry, University of California, San Francisco, California, 94143-0724, USA

    Christopher Martin, Seymour Packman & Jane Gitschier

  3. Department of Pediatrics, University of California, San Francisco, California, 94143-0724, USA

    Barbara Levinson & Jane Gitschier

  4. The Howard Hughes Medical Institute, University of California, San Francisco, California, 94143-0724, USA

    Christopher Vulpe

  5. Department of Biology, Northern Michigan University, Marquette, Michigan, 49855, USA

    Frank Verley

Authors
  1. Barbara Levinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christopher Vulpe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bruce Elder
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christopher Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Frank Verley
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Seymour Packman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jane Gitschier
    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

Levinson, B., Vulpe, C., Elder, B. et al. The mottled gene is the mouse homologue of the Menkes disease gene. Nat Genet 6, 369–373 (1994). https://doi.org/10.1038/ng0494-369

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0494-369

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