Regulation of Copper Metabolism in the Mottled Mouse

Abstract

Menkes' kinky-hair syndrome is an X-linked recessive neurodegenerative and connective-tissue disorder, with decreased serum copper and ceruloplasmin-copper oxidase concentrations and tissue-specific increases in copper content. Clinical manifestations can be related to relative copper deficiency and reduced activity of cuproenzymes in multiple organs. An animal model is provided by mice hemizygous for mutant alleles, such as the blotchy allele, at the X-linked mottled locus. This locus may be homologous in mouse and man. The basic defect is unknown but has been thought to reside in the regulation of the function or synthesis of metallothioneins. In the blotchy mouse and in cultured skin fibroblasts derived therefrom, we showed that the mutation specifically affects the metabolism of copper and not other trace metals. Excessive accumulation and abnormal (reduced) exit kinetics were demonstrated for copper but not for the related trace metals cadmium and zinc. While metallothionein-I messenger RNA (mRNA) concentrations were elevated in blotchy fibroblasts, the elevations in metallothionein-I mRNA in response to metallothionein inducers (cadmium, copper) were similar in blotchy and control cells. Further, metallothionein-I mRNA levels were indistinguishable in mutant and control fibroblasts containing equivalent intracellular copper concentrations. Finally, metallothionein-I mRNA content was not elevated in blotchy kidneys at early developmental stages, before storage of excessive copper. The aggregate data suggest that the basic defect in the blotchy mouse--and, by analogy, in Menkes' syndrome--does not reside in defective modulation of metallothionein function and does not cause abnormal regulation of metallothionein synthesis.

Molecular mechanisms of copper metabolism and the role of the Menkes disease protein

“…The observation that Mo br males had decreased levels of copper in the brain led to the proposition that the mottled locus was involved in copper metabolism and that the symptoms in mottled mutants arose out of the deficiency of copper enzymes as a consequence of primary copper deficiency (75). Cells from mottled mutants in culture from a number of tissue types, except liver, exhibit a defect in copper export with concomitant cytosolic copper accumulation (76)(77)(78). Systemic copper deficiency in mottled mutants results from the accumulation of copper in the intestines and kidneys leading to a failure of copper delivery to other tissues (79); consequently, most organs have reduced activity of copper-dependent enzymes.…”