PMID:8640230

Citation	Kelly, EJ and Palmiter, RD (1996) A murine model of Menkes disease reveals a physiological function of metallothionein. Nat. Genet. 13:219-22
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 ATP7A. 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). 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-/-). 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 tissues 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.
Links	PubMed Online version:10.1038/ng0696-219
Keywords	Adenosine Triphosphatases/genetics; Animals; Base Sequence; Carrier Proteins/genetics; Cation Transport Proteins; Cell Survival; Cells, Cultured; Copper/deficiency; Copper/metabolism; Crosses, Genetic; Culture Media; Disease Models, Animal; Embryo, Mammalian/cytology; Embryo, Mammalian/pathology; Female; Fetal Death/genetics; Intestines/chemistry; Intestines/metabolism; Liver/chemistry; Liver/metabolism; Male; Menkes Kinky Hair Syndrome/genetics; Metallothionein/genetics; Metallothionein/physiology; Mice; Mice, Inbred Strains; Molecular Sequence Data; Recombinant Fusion Proteins; Tissue Distribution; X Chromosome
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