Defective localization of the Wilson disease protein (ATP7B) in the mammary gland of the toxic milk mouse and the effects of copper supplementation

Abstract

Toxic milk (tx) is a copper disorder of mice that causes a hepatic accumulation of copper similar to that seen in patients with Wilson disease.Both disorders are caused by a defect in the ATP7B copper-transporting ATPase.A feature of the tx phenotype is the production of copper-deficient milk by lactating dams homozygous for the tx mutation ; the milk is lethal to the pups.It has not been determined whether the production of copperdeficient milk is a direct consequence of impaired expression of ATP7B protein in the mammary gland.With the use of immunohistochemistry, our study demonstrated that the ATP7B protein was mislocalized in the lactating tx mouse mammary gland, which would explain the inability of the tx mouse to secrete normal amounts of copper in milk.Confocal microscopy analysis showed that, in the lactating tx mammary gland, ATP7B was predominantly perinuclear in comparison with the diffuse, cyto-