CORRECTION OF THE COPPER TRANSPORT DEFECT OF MENKES PATIENT FIBROBLASTS BY EXPRESSION OF THE MENKES AND WILSON ATPASES

Menkes' disease is a fatal, X-linked, copper deficiency disorder that results hom defective copper efflux from intestinal cells and inadequa te copper delivery to other tissues, leading to deficiencies of critic al copper-dependent enzymes. Wilson's disease is an autosomally inheri ted, copper toxicosis disorder resulting from defective biliary excret ion of copper, which leads to copper accumulation in the liver. The AT P7A and ATP7B genes that are defective in patients with Menkes' and Wi lson's diseases, respectively, encode transmembrane, P-type ATPase pro teins (ATP7A or MNK and ATP7B or WND, respectively) that function to t ranslocate copper across cellular membranes. In this study, the cDNAs derived from a normal human ATP7A gene and the murine ATP7B homologue, Atp7b, were separately transfected into an immortalized fibroblast ce ll line obtained from a Menkes' disease patient. Both MNK and WND expr essed from plasmid constructs were able to correct the copper accumula tion and copper retention phenotype of these cells. However, the two p roteins responded differently to elevated extracellular copper levels, Although MNK showed copper-induced trafficking from the trans-Golgi n etwork. to the plasma membrane, in the same cell line the intracellula r location of WND did not appear to be affected by elevated copper.