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A novel gene involved in zinc transport is deficient in the lethal milk mouse

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Abstract

We have identified the gene responsible for the inherited zinc deficiency in the lethal milk (Im) mouse. The gene, here designated Znt4, encodes a 430-amino-acid protein that is homologous to two proteins, ZnT2 and ZnT3, responsible for sequestration of zinc into endosomal/lysosomal compartments and synaptic vesicles, respectively. We show that the Znt4 gene confers zinc resistance to a zinc-sensitive yeast strain and that it is abundantly expressed in the mammary epithelia and brain. The lethal milk mutant has a nonsense mutation at arginine codon 297 in the Znt4 gene.

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References

  1. Vallee, B.L. & Falchuk, K.H. The biochemical basis of zinc physiology. Physiol. Rev. 73, 79–118 (1993).

    Article  CAS  Google Scholar 

  2. Palmiter, R.D. & Findley, S.D. Cloning and functional characterization of a mammalian zinc transporter that confers resistance to zinc. EMBOJ. 14, 639–649 (1995).

    Article  CAS  Google Scholar 

  3. Palmiter, R.D., Cole, T.B. & Findley, S.D., ZnT2, a mammalian protein that confers resistance to zinc by facilitating vesicular sequestration. EMBO J. 15, 1784–1791 (1996).

    Article  CAS  Google Scholar 

  4. Palmiter, R.D., Cole, T.B., Quaife, C.J. & Findley, S.D., ZnT3, a putative transporter of zinc into synaptic vesicles. Proc. Natl. Acad. Sci. USA 93, 14934–14939 (1996).

    Article  CAS  Google Scholar 

  5. Kamizono, A., Nishizawa, M., Y, Murata,, K. & Kimura,, A. Identification of a gene conferring resistance to zinc and cadmium ions in the yeast Saccharamyces cerevisiae . Mol. Gen. Genet. 219, 161–167 (1989).

    Article  CAS  Google Scholar 

  6. Conklin, D.S., McMaster, J.A., Culbertson, M.R. & Kung, C. COT1, a gene involved in cobalt accumulation in Saccharomyces cerevisiae. Mol. Cell. Biol. 12, 3678–3688 (1992).

    Article  CAS  Google Scholar 

  7. Nies, D.H., Nies, A., Chu, L. & Silver, S. Expression and nucleotide sequence of a plasmid-determined divalent cation efflux system from Alcaligenes eutrophus. Proc. Nat. Acad. Sci. USA 86, 7351–7355 (1989).

    Article  CAS  Google Scholar 

  8. Zhao, H. & Hide, D. The yeast ZRT1 gene encodes the zinc transporter protein of a high-affinity uptake system induced by zinc limitation. Proc. Natl. Acad. Sci. USA 93, 2454–2458 (1996).

    Article  CAS  Google Scholar 

  9. Zhao, H. & Eide, D. The ZRT2 gene encodes the low affinity zinc transporter in Saccharomyces cervisiae. J. Biol. Chem. 271, 23202–23210 (1996).

    Google Scholar 

  10. van Wouwe,, J.P. Clinical and laboratory diagnosis of acrodermatitis enteropathica. Eur. J. Pediatr. 149, 2–8 (1989).

    Article  CAS  Google Scholar 

  11. Piletz, J.E. & Ganschow, R.E. Zinc deficiency in murine milk underlies expression of the lethal milk (Im) mutation. Science 199, 181–183 (1978).

    Article  CAS  Google Scholar 

  12. Ackland, M.L. & Mercer, J.F.B. The murine mutation, lethal milk, results in production of zinc-deficient milk. J. Nutrition 122, 1214–1218 (1992).

    Article  CAS  Google Scholar 

  13. Lee, D.Y., Shay, N.F. & Cousins, R.J. Altered zinc metabolism occurs in murine lethal milk syndrome. J. Nutrition 122, 2233–2238 (1992).

    Article  CAS  Google Scholar 

  14. Erway, L.C. & Grider, A. Zinc metabolism in lethal milk mice: otolith, lactation, and aging effects. J. Heredity 75, 480–484 (1984).

    Article  CAS  Google Scholar 

  15. Piletz, J.E. & Ganschow, R.E. Lethal milk mutations results in dietary zinc deficiency in nursing mice. Am. J. Clin. Nutr. 31, 560–562 (1978).

    Article  CAS  Google Scholar 

  16. Dickie, M.M., Mouse News Letter 41, 30 (1969).

    Google Scholar 

  17. Green, M.C. & Sweet, H.O., News Letter 49, 32 (1973).

    Google Scholar 

  18. Roberts, E. A new mutation in the house mouse (Mus musculus). Science 74, 569 (1931).

    Article  CAS  Google Scholar 

  19. Siracusa, L.D., Morgan, J.L., Fisher, J.K., Abbott, C.M. & Peters, J. Mouse chromosome 2. Mamm. Genome 6,, S51–S63 (1996).

    Google Scholar 

  20. Robinson, P.J. et al. Location of the mouse β2-microglobulin gene B2m determined by linkage analysis. Immunogenetics 14, 449–452 (1981).

    Article  CAS  Google Scholar 

  21. White, R.A. et al. The murine pallid mutation is a platelet storage pool disease associated with the protein 4.2 (pallidin) gene. Nature Genet. 2, 80–83 (1992).

    Article  CAS  Google Scholar 

  22. Gwynn, B., Ciciotte, S., Korsgren, C., Cohen, C.M. & Peters, L.L. Genetic mapping distinguishes the gene encoding protein 4.2 from the mouse platelet storage pool deficiency mutation pallid. Mol. Biol. Cell 7, 550a (1996).

    Google Scholar 

  23. Lyon, M.F. & Searle, A.G. Variants and Strains of the Laboratory Mouse (Oxford University Press, Oxford, UK, 1989).

  24. von Heijne,, G. Membrane proteins: from sequence to structure. Annu. Rev. Biophys. Biomol. Struct. 23, 167–192 (1994).

    Article  CAS  Google Scholar 

  25. Purichia, N. & Erway, L.C. Effects of dichlorophenamide, zinc, and manganese on otolith development in mice. Dev. Biol. 27, 395–405 (1972).

    Article  CAS  Google Scholar 

  26. Kuramoto, Y., Igarashi, Y. & Tagami, H. Acquired zinc deficiency in breast-fed infants. Semin. Dermatol. 10, 309–312 (1991).

    CAS  PubMed  Google Scholar 

  27. Glover, M.T. & Atherton, D.J. Transient zinc deficiency in two full-term breast-fed siblings associated with low maternal breast milk zinc concentration. Pediatr. Dermatol. 5, 10–13 (1988).

    Article  CAS  Google Scholar 

  28. Eckhert, C.D., Sloan, M.V., Duncan, J.R. & LS.Zinc binding: a difference between human and bovine milk. Science 195, 789 (1977).

    Article  CAS  Google Scholar 

  29. Moynahan, E.J. Acrodermatitis enteropahtic: a lethal inherited human zinc-deficiency disorder. Lancet II, 399–400 (1974).

    Article  Google Scholar 

  30. Theophilos, M.B., Cox, D.W. & Mercer, J.F.B. The toxic milk mouse is a murine model of Wilson disease. Hum. Mol. Genet. 5, 1619–1624 (1996).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  32. Chaplin, D.D. & Brownstein, B.H., Protocols in Molecular Biology (ed. Janssen, K.) 6.10.1–6.10.9 (John Wiley & Sons, New York, 1994).

    Google Scholar 

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Huang, L., Gitschier, J. A novel gene involved in zinc transport is deficient in the lethal milk mouse. Nat Genet 17, 292–297 (1997). https://doi.org/10.1038/ng1197-292

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