title: A murine model of Menkes disease reveals a physiological function of metallothionein.
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.
authors.affiliation: Department of Biochemistry, University of Washington, Seattle 98195-7370, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Kelly
authors.forename: R D
authors.initials: RD
authors.lastname: Palmiter
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics; D027682:Cation Transport Proteins; D002470:Cell Survival; D002478:Cells, Cultured; D003300:Copper / Q000172:deficiency / Q000378:metabolism*; D000073840:Copper-Transporting ATPases; D003433:Crosses, Genetic; D003470:Culture Media; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000166:cytology / Q000473:pathology; D005260:Female; D005313:Fetal Death / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000737:chemistry; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008297:Male; D007706:Menkes Kinky Hair Syndrome / Q000235:genetics*; D008668:Metallothionein / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D011993:Recombinant Fusion Proteins; D014018:Tissue Distribution; D014960:X Chromosome
chemical_list: C486201:Atp7a protein, mouse; D002352:Carrier Proteins; D027682:Cation Transport Proteins; D003470:Culture Media; D011993:Recombinant Fusion Proteins; D003300:Copper; D008668:Metallothionein; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases