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Abnormal Copper-Thionein Synthesis and Impaired Copper Utilization in Mutated Brindled Mice: Model for Menkes' Disease

Interuniversity Reactor Institute, Mekelweg 15, 2629 JB DELFT, The Netherlands

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.

KEY WORDS: • copper-thionein • Brindled mice • Menkes' disease

Manuscript received 14 May 1979.