Metallothionein and the development of the mottled disorder in the mouse.

Copper accumulates in kidney tissue of mottled (Mo) mice largely in association with a low MW cytosol protein, and the reduced copper levels in neonatal mutant liver are largely the result of a reduction in the amount of copper associated with this same protein. On the basis of ion-exchange chromatographic profile, heat stability, absence of a 280nm absorption peak, and the binding of Cd109 and Zn65 the protein mutants in the kidney is identified as metallothionein (MT). Amino acid analysis, however, failed to confirm this, and it is suggested that the high copper content of the mutant protein results in its oxidative degradation during purification, even when normal anaerobic precautions are taken. Estimates of thionein protein content of tissues from mutant and normal mice demonstrated that the levels are significantly elevated in both young and adult mutant kidney and depressed in young mutant liver, in parallel therefore with the changes in tissue copper levels. In adult mutant liver tissue, however, thionein levels are significantly raised, even though tissue copper content is normal. The synthesis and degradation of MT was examined in some detail. Incorporation of S35-cysteine in kidney MT was significantly raised in both young and adult mutant mice, while in adult tissue the rate of degradation of MT was significantly depressed. The elevated kidney MT levels arise therefore in young mutant mice from an increased rate of synthesis and in adult mice from the combined effects of increased synthesis and reduced degradation.