Evidence That Single Missense Mutations in the Atp7a Gene of Two Mouse Models for Menkes' Disease Are Responsible for Impaired Copper Transport.

Menkes' disease is an inherited disorder of copper homeostasis that arises from a deficiency in copper-transporting P-type ATPase, the mouse gene for which is designated Atp7a. The macular and the viable-brindled mouse are among Menkes' disease models and have been shown to have respective single missense mutations in their genes. In this study we tested whether these mutations are a cause of the disease. Yeast strain Δccc2, lacking CCC2, the yeast homologue of Atp7a, was used to examine whether this mutant yeast can be rescued by expression of acular or viable-brindled Atp7a protein when cultured in copper- and iron-deficient medium. Expression of both mutant Atp7a proteins was found to enable the growth of Δccc2 yeast, but the growth rates were less than one-fifth of the rate observed for Δccc2 yeast expressing wild-type Atp7a protein. Thus it is clear that the missense mutations of both animal models for Menkes' disease are responsible for the impaired function of copper transport.