Autoradiographic demonstration of the copper-accumulating tissues in mice with a defect homologous to Menkes' Kinky Hair disease.

Mutated Brindled mice have a genetic defect homologous to the human disorder Menkes' or Kinky Hair disease. These animals were used to survey the tissues in which copper accumulates as result of this defect. Heterozygous and unaffected animals were i.p. injected with radio-copper (64Cu). Sites of pathological 64Cu accumulation were visualized by whole body autoradiography. Apart from the tissues already known to accumulate copper, particularly the kidneys, pathological accumulations were also found in a number of other tissues. It is concluded that in Menkes' disease copper accumulates in epithelioid cells.

Menkes' kinky hair disease. I. Comparison of classical and unusual clinical and biochemical features in two patients.

Two patients with Menkes' kinky hair disease were examined. Both showed the characteristic clinical features of this disease in combination with a low plasma-copper level. However, for one of them, studies with 64Cu provided clues that the copper was handled in a way unusual for a Menkes patient, viz., incorporation of 64Cu into ceruloplasmin during an oral 64Cu-loading test and abnormal behavior of skin fibroblasts in in vitro experiments. A comparison with brindled mice and some clinical aspects, viz., the age at death, the quality of the hair and the macrocephaly, of both patients are discussed.

Abnormal copper-thionein synthesis and impaired copper utilization in mutated brindled mice: model for Menkes' disease.

The copper utilization in mutated Brindled mice is impaired. Copper accumulates in various tissues, e.g., the kidney, of the mutated mice. The renal copper binding protein is characterized as copper-thionein--metallothionein to which copper is bound. The L-[35S]cystine incorporation experiments without prior induction with copper revealed an abnormal synthesis of metallothionein in the mutated mice. Two models are proposed which link the abnormal metallothionein synthesis with an impaired copper utilization. Model 1 is an unrestrained translation of renal mRNA which codes for metallothionein. Model 2 is an impaired renal copper reabsorption resulting in a toxic intracellular copper concentration which induces metallothionein synthesis to sequester copper. The impaired copper utilization results in a fatal copper deficiency in "Menkes" Brindled mice.

Primary biochemical defect in copper metabolism in mice with a recessive X-linked mutation analogous to Menkes' disease in man.

The defect in Menkes' disease in man is identical to that in Brindled mice. The defect manifests itself in a accumulation of copper in some tissues, such as renal, intestinal (mucosa and muscle), pancreatic, osseous, muscular, and dermal. Hence a fatal copper deficiency results in other tissues (e.g., hepatic). The copper transport through the intestine is impaired and copper, which circumvents the block in the copper resorption, is irreversibly trapped in the above-mentioned, copper accumulating tissues where it is bound to a cytoplasmatic protein with molecular weight 10,000 daltons, probably the primary cytoplasmatic copper transporting protein. This protein shows a Cu-S absorption band at 250 nm, and the copper:protein ratio is increased. Such copper rich protein was found neither in the kidneys of the unaffected mice nor in the liver of the mice that do have the defect. Three models of the primary defect in Menkes disease are proposed.