A Murine Model of Menkes Disease Reveals a Physiological Function of Metallothionein

Nat Genet. 1996 Jun;13(2):219-22. doi: 10.1038/ng0696-219.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Animals
  • Base Sequence
  • Carrier Proteins / genetics
  • Cation Transport Proteins*
  • Cell Survival
  • Cells, Cultured
  • Copper / deficiency
  • Copper / metabolism*
  • Copper-Transporting ATPases
  • Crosses, Genetic
  • Culture Media
  • Disease Models, Animal*
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / pathology
  • Female
  • Fetal Death / genetics
  • Intestinal Mucosa / metabolism
  • Intestines / chemistry
  • 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


  • Atp7a protein, mouse
  • Carrier Proteins
  • Cation Transport Proteins
  • Culture Media
  • Recombinant Fusion Proteins
  • Copper
  • Metallothionein
  • Adenosine Triphosphatases
  • Copper-Transporting ATPases