Menkes' disease: abnormal metallothionein gene regulation in response to copper

Menkes' disease, an inherited disorder of copper metabolism, is characterized by the accumulation of excess copper-metallothionein in certain tissues and cell types. Using cultured fibroblasts, we show that this is due to the ability of low concentrations of copper to induce metallothionein mRNA synthesis in Menkes' but not normal cells. We also show that copper, which is unusually toxic to Menkes' cells, induces the synthesis of 84 kd and 68 kd polypeptides tentatively identified as heat shock proteins. Transfection experiments with a cloned metallothionein fusion gene show that this is due to a defect in a diffusible factor involved in either metallothionein gene transcriptional regulation or copper metabolism.