The pathology and trace element status of the toxic milk mutant mouse

The toxic milk (tx) mouse is a mutant in which copper metabolism is abnormal. Homozygous tx adults do not show overt signs of disease, but litters born to such parents are deficient in copper and die at about 2 weeks of age unless copper is provided. The results reported here clearly indicate that adults accumulate copper in the liver, kidney, spleen, brain, muscle, serum and red blood cells. The concentration of zinc is also elevated in liver, brain and muscle. In adult animals there is damage to hepatocytes with marked changes to the nuclei. Haemolysis occurs with subsequent deposition of haemosiderin in the kidney. This mutant provides a useful model for studies of the pathogenesis and treatment of copper toxicity in animals and man

Functional studies on the Wilson copper P-Type ATPase and toxic milk mouse mutant

The Wilson protein (WND; ATP7B) is an essential component of copper homeostasis. Mutations in the ATP7B gene result in Wilson disease, which is characterised by hepatotoxicity and neurological disturbances. In this paper, we provide the first direct biochemical evidence that the WND protein functions as a copper-translocating P-type ATPase in mammalian cells. Importantly, we have shown that the mutation of the conserved Met1386 to Val, in the Atp7B for the mouse model of Wilson disease, toxic milk (tx), caused a loss of Cu-translocating activity. These investigations provide strong evidence that the toxic milk mouse is a valid model for Wilson disease and demonstrate a link between the loss of catalytic function of WND and the Wilson disease phenotype.<br /