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Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper–transporting ATPase

A Correction to this article was published on 01 March 1993

Abstract

Menkes disease is an X–linked disorder of copper transport characterized by progressive neurological degeneration and death in early childhood. We have isolated a candidate gene (Mc1) for Menkes disease and find qualitative or quantitative abnormalities in the mRNA in sixteen of twenty–one Menkes patients. Four patients lacking Mc1 RNA showed rearrangements of the Menkes gene. The gene codes for a 1,500 amino acid protein, predicted to be a P–type cation–transporting ATPase. The gene product is most similar to a bacterial copper–transporting ATPase and additionally contains six putative metal–binding motifs at the N–terminus. The gene is transcribed in all cell types tested except liver, consistent with the expression of the Menkes defect.

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References

  1. Danks, D.M. in The Metabolic Basis of Inherited Disease (eds Scrives, C., Beaudet, A., Sly, W. & Valle, D.) 1411–1432 (McGraw-Hill, New York, 1989).

    Google Scholar 

  2. van den Berg, G.J., et al. Muscle cell cultures in Menkes' disease: Copper accumulation in myotubes. J. Inher. metab. Dis. 13, 207–211 (1990).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Darwish, H.M., Hoke, J.E. & Ettinger, M.J. Kinetics of Cu(ll) 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 

  5. Tonneson, T. & Horn, N. Prenatal and postnatal diagnosis of Menkes' disease, an inherited disorder of copper metabolism. J. Inher. metab. Dis. 12, 207–214 (1989).

    Article  Google Scholar 

  6. Kapur, S., Higgin, J.V., Delp, K. & Rogers, B. Menkes syndrome in a girl with X-autosome translocation. Am. J. med. Genet. 26, 503–510 (1987).

    Article  CAS  Google Scholar 

  7. Tonnesen, T. et al. Multi-point linkage analysis in Menkes disease. Am. J. hum. Genet. 50, 1012–1017 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Tumer, Z., et al. Mapping of the Menkes locus to Xq13.3 distal to the X-inactivation center by an intrachromosomal insertion of the segment Xq13.3-q21.2. Hum. Genet. 88, 668–672 (1992).

    Article  CAS  Google Scholar 

  9. Davisson, M.T., Roderick, T.H. & Doolittle, D.P. in Genetic variants and strains of the laboratory mouse (eds Lyon, M.F. & Searle, A.G.) 432–505 (Oxford University Press, 1990).

    Google Scholar 

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

    Article  CAS  Google Scholar 

  11. Verga, V., et al. Localization of the translocation breakpoint in a female with Menkes syndrome to Xq13.2. Am. J. hum. Genet. 48, 1133–1138 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Riley, J., et al. A novel, rapid method for the isolation of terminal sequences from yeast artificial chromosome (YAC) clones. Nucl. Acids Res. 18, 2887–2890 (1990).

    Article  CAS  Google Scholar 

  13. Nelson, D.L., et al. Alu polymerase chain reaction: A method for rapid isolation of human-specific sequences from complex DNA sources. Proc. natn. Acad. Sci. U.S.A. 86, 6686–6690 (1989).

    Article  CAS  Google Scholar 

  14. Tumer, 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  CAS  Google Scholar 

  15. Buckler, A.J., et al. Exon amplification: A strategy to isolate mammalian genes based on RNA splicing. Proc. natn. Acad. Sci. U.S.A. 88, 4005–4009 (1991).

    Article  CAS  Google Scholar 

  16. Richards, R.I. & Sutherland, G.R. Heritable unstable DNA sequences. Nature Genet. 1, 7–9 (1992).

    Article  CAS  Google Scholar 

  17. Oedermatt, A., Suter, H., Kraps, R. & Solioz, M. An ATPase operon involved in copper resistance by Enterococcus hirae. Ann. N.Y. Acad. Sci. (in the press).

  18. Solioz, M., Mathews, S. & Furst, P. Cloning of the K+-ATPase of Streptococcus faecalis. J. biol. Chem. 262, 7358–7362 (1987).

    CAS  PubMed  Google Scholar 

  19. 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 

  20. Ivey, D.M., et al. The cadC gene product of alkaliphilic 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  CAS  Google Scholar 

  21. Hesse, J.E., et al. Sequence homology between two membrane transport ATPases, the Kdp-ATPase of Escherichia coli and the Ca2+-ATPase of sarcoplasmic reticulum. Proc. natn Acad. Sci. U.S.A. 81, 4746–4750 (1984).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  23. Shull, G.E., Schwartz, A. & Lingrel, J.B. Amino-acid sequence of the catalytic subunit of the (Na+ +K+) ATPase deduced from a complementary DNA. Nature 316, 691–695 (1985).

    Article  CAS  Google Scholar 

  24. Brandl, C.J., Green, N.M., Korczak, B. & MacLennan, D.H. Two Ca2+ ATPase genes: Homologies and mechanistic implications of deduced amino acid sequences. Cell 44, 597–607 (1986).

    Article  CAS  Google Scholar 

  25. Serrano, R. Structure and function of proton translocating ATPase in plasma membranes of plants and fungi. Biochim. Biophys. Acta 947, 1–28 (1988).

    Article  CAS  Google Scholar 

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

    CAS  Google Scholar 

  27. MacLennan, D.H. Molecular tools to elucidate problems in excitation-contraction coupling. Biophys. J. 58, 1355–1365 (1990).

    Article  CAS  Google Scholar 

  28. Wach, A., Schlesser, A. & Goffeau, A. An alignment of 17 deduced protein sequences from plant, fungi, and ciliate H+-ATPase genes. J. Bioenerg. Biomem. 24, 309–317 (1992).

    CAS  Google Scholar 

  29. Portillo, F. & Serrano, R. Dissection of functional domains of the yeast proton-pumping ATPase by directed mutagenesis. EMBO J. 7, 1793–1798 (1988).

    Article  CAS  Google Scholar 

  30. Portillo, F. & Serrano, R. Growth control strength and active site of yeast plasma membrane ATPase studied by site-directed mutagenesis. Eur. J. Biochem. 186, 501–507 (1989).

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  32. Clarke, D.M., Loo, T.W. & MacLennan, D.H. Functional consequences of alterations to polar amino acids located in the transmembrane domain of the Ca++-ATPase of sarcoplasmic reticulum. J. biol. Chem. 265, 6262–6267 (1990).

    CAS  PubMed  Google Scholar 

  33. Silver, S. & Walderhaug, M. Gene regulation of plasmid- and chromosome-determined inorganic ion transport in bacteria. Microbiol. Rev. 56, 195–228 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Waldrop, G.L., Palida, F.A., Hadi, M., Lonergan, P.A. & Ettinger, M.J. Effect of albumin on net copper accumulation by fibroblasts and hepatocytes. Am. Physiol. Soc. 259, G219–G224 (1990).

    CAS  Google Scholar 

  35. Packman, S., O'Toole, C., Price, D. & Thaler, M. Cadmium zinc and copper metabolism in the Mottle mouse, an animal model for Menkes' kinky hair syndrome. J. Inorg. Biochem. 19, 203–211 (1983).

    Article  CAS  Google Scholar 

  36. Packman, S. & O'Toole, C. Trace metal metabolism in cultured skin fibroblasts of the Mottled mouse: response to metallothionein inducers. Ped. Res. 18, 1282–1286 (1984).

    Article  CAS  Google Scholar 

  37. 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  Google Scholar 

  38. Packman, S., Sample, S. & Whitney, S. Defective intracellular copper translocation in Menkes' kinky hair syndrome. Ped. Res. 21, 293 (1987).

    Article  Google Scholar 

  39. Kuivaniemi, H., Peltonen, L., Palotie, A., Kaitila, I. & Kavirikko, K. Abnormal copper metabolism and deficient lysyl oxidase activity in a heritable connective tissue disorder. J. clin. Invest. 69, 730–733 (1981).

    Article  Google Scholar 

  40. 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  Google Scholar 

  41. Waldrop, G.L. & Ettinger, M.J. The relationship of excess copper accumulation by fibroblasts from the brindled mouse model of Menkes disease to the primary defect. Biochem. J. 267, 417–422 (1990).

    Article  CAS  Google Scholar 

  42. Cha, J.-S. & Cooksey, D.A. Copper resistance in Pseudomonas syringae mediated by periplasmic and outer membrane proteins. Proc. natn. Acad. Sci. U.S.A. 88, 8915–8919 (1991).

    Article  CAS  Google Scholar 

  43. Rogers, S.D., Bhave, M.R., Mercer, J.F.B., Camakaris, J. & Lee, B.T.O. Cloning and characterization of cutE, a gene involved in copper transport in Escherichia coli. J. Bacteriol. 173, 6742–6748 (1991).

    Article  CAS  Google Scholar 

  44. Brown, N.L., Rouch, D.A. & Lee, T.O. Copper resistance determinants in bacteria. Plasmid 27, 41–51 (1992).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

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

    Article  CAS  Google Scholar 

  48. Murnane, J.P., Fuller, L.F. & Painter, R.B. Establishment and characterization of a permanent pSV ori-transformed ataxia-telangiectasia cell line. Exp. Cell Res. 158, 119–126 (1985).

    Article  CAS  Google Scholar 

  49. Levinson, B., et al. A transcribed gene in an intron of the human factor VIII gene. Genomics 7, 1–11 (1990).

    Article  CAS  Google Scholar 

  50. Marchuk, D.A. & Collins, F.S. in YAC libraries: A user's guide (eds. Nelson, D. & Brownstein, B.) (W.H. Freeman, New York) (in the press).

  51. Kovalic, D., Kwak, J. & Weisblum, B. General method for direct cloning of DNA fragments generated by primed enzymatic amplification. Nucl. Acids Res. 19, 4560–4563 (1991).

    Article  CAS  Google Scholar 

  52. 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  Google Scholar 

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

    Article  CAS  Google Scholar 

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Vulpe, C., Levinson, B., Whitney, S. et al. Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper–transporting ATPase. Nat Genet 3, 7–13 (1993). https://doi.org/10.1038/ng0193-7

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