Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes

Prim de Bie ^1*, Patricia A.J. Muller ¹, Cisca Wijmenga ² and Leo W.J. Klomp ¹

¹ University Medical Center Utrecht, Netherlands
² University Medical Center Utrecht/University Medical Center Groningen, Netherlands

^* To whom correspondence should be addressed. E-mail: p.debie{at}umcutrecht.nl.

Accepted 15 August 2007

Abstract

The trace metal copper is essential for a variety of biological processes, but extremely toxic when present in excessive amounts. Therefore, concentrations of this metal are kept within a tight balance. Central regulators of cellular copper metabolism are the copper transporting P-type ATPases ATP7A and ATP7B. Mutations in ATP7A or ATP7B disrupt the homeostatic copper balance resulting in copper deficiency (Menkes disease) or copper overload (Wilson disease), respectively. ATP7A and ATP7B exert their functions in copper transport through a variety of interdependent mechanisms and regulatory events, including their catalytic ATPase activity, copper-induced trafficking, post-translational modifications and protein-protein interactions. Here we will review the extensive efforts that have been undertaken over the last few years to dissect and characterize these mechanisms, and how these are affected in Menkes and Wilson disease. As both disorders are characterized by an extensive clinical heterogeneity, we will discus how the underlying genetic defects correlate with the molecular functions of ATP7A and ATP7B and with the clinical expression of these disorders.

Keywords: ATP7A, ATP7B, Copper homeostasis, Menkes Disease, Wilson Disease

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