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A murine model of Menkes disease reveals a physiological function of metallothionein

Nature Genetics volume 13, pages 219–222 (1996)Cite this article

Abstract

Human Menkes disease and the murine Mottled phenotype are X-linked diseases that result from copper deficiency due to mutations in a copper-effluxing ATPase, designated ATP7A1–5. Male mice with the Mottled-Brindled allele (Mo-brJ) accumulate copper in the intestine, fail to export copper to peripheral organs and die a few weeks after birth. Much of the intestinal copper is bound by metallothionein (MT)6. To determine the function of MT in the presence of Atp7a deficiency, we crossed Mo-brJ females with males that bear a targeted disruption of the Mt1 and Mt2 genes (Mt −/−)7. On an Mt −/− background, most Mo-brJ males as well as heterozygous Mo-brJ females die before embryonic day 11. The lethality in Mo-brJ females can be explained by preferential inactivation of the paternal X chromosome in extraembryonic tissues8 and resultant copper toxicity in the absence of MT. In support of this hypothesis, cell lines derived from Mt−/−, Mo-brJ embryos are very sensitive to copper toxicity.

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Authors and Affiliations

  1. Department of Biochemistry and Howard Hughes Medical Institute, University of Washington, Box 357370, Seattle, Washington, 98195-7370, USA

    Edward J. Kelly & Richard D. Palmiter

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  1. Edward J. Kelly
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  2. Richard D. Palmiter
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Kelly, E., Palmiter, R. A murine model of Menkes disease reveals a physiological function of metallothionein. Nat Genet 13, 219–222 (1996). https://doi.org/10.1038/ng0696-219

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