The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene

Abstract

Wilson disease (WD) is an autosomal recessive disorder characterized by the toxic accumulation of copper in a number of organs, particularly the liver and brain. As shown in the accompanying paper, linkage disequilibrium & haplotype analysis confirmed the disease locus to a single marker interval at 13q14.3. Here we describe a partial cDNA clone (pWD) which maps to this region and shows a particular 76% amino acid homology to the Menkes disease gene, Mc1. The predicted functional properties of the pWD gene together with its strong homology to Mc1, genetic mapping data and identification of four independent disease-specific mutations, provide convincing evidence that pWD is the Wilson disease gene.

Identification of a novel Wilson disease gene mutation frequent in Upper Austria: a genetic and clinical study

“…ATP7b-a copper transporting P-type ATPase-is the gene product of the WD gene. [5][6][7] ATP7b resides mainly in hepatocytes in the trans-Golgi network, transporting copper for incorporation into apoceruloplasmin and excretion into the bile. 8 More than 500 distinct mutations in the ATP7B gene, including missense and nonsense mutations, insertions and deletions, have been described.…”

Raft-mediated Trafficking of Apical Resident Proteins Occurs in Both Direct and Transcytotic Pathways in Polarized Hepatic Cells: Role of Distinct Lipid Microdomains

“…ATP7B is a copper-transporting P-type ATPase with eight putative TMD, and in response to copper, relocates from the TGN to the BC surface in HepG2 cells (Bull et al, 1993;Tanzi et al, 1993;Roelofsen et al, 2000). Analogous to MDR1 (see above) and consistent with a direct transport pathway, no ATP7B could be detected at the BL membrane at steady state (our unpublished data).…”

Distinct Wilson’s Disease Mutations in ATP7B Are Associated With Enhanced Binding to COMMD1 and Reduced Stability of ATP7B

“…Within its amino terminal region, ATP7B contains six copper binding sequences, through which it receives copper by a transient copper-dependent interaction with the copper chaperone ATOX1 7,8 . Whereas incubation with the copper chelator BCS efficiently prevented interaction of ATP7B-Flag and ATOX1-GST ( Figure 2B, compare lanes 6 and 12), no reproducible effects of CuSO 4 or BCS incubation on the interaction of COMMD1-GST with ATP7B-Flag were observed ( Figure 2B, compare lanes 4 and 10). These data suggest that COMMD1 binds to the amino terminus of ATP7B, independently of cellular copper levels.…”

“…The clinical presentation of WD is highly heterogeneous, and usually includes hepatic and/or neurological abnormalities due to toxic accumulation of copper in the liver and the brain 2 . WD is caused by mutations in the ATP7B gene, which encodes a copper transporting P-type ATPase [3][4][5][6] . ATP7B plays a key role in hepatic copper excretion, by virtue of its ability to transport copper across cellular membranes at the cost of ATP hydrolysis.…”