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

¹ Laboratory of Metabolic and Endocrine Diseases, University Medical Center, Utrecht, The Netherlands
² Complex Genetics Section, DBG-Department of Medical Genetics, University Medical Center, Utrecht, The Netherlands
³ Department of Genetics, University Medical Center, Groningen, The Netherlands

Correspondence to:
L W J Klomp, Laboratory of Metabolic and Endocrine Diseases, Room KC.02.069.1, Lundlaan 6, 3584 EA Utrecht, The Netherlands; l.klomp{at}umcutrecht.nl]

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 in the body are kept under tight control. 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. This paper reviews the extensive efforts that have been undertaken over the past few years to dissect and characterise these mechanisms, and how these are affected in Menkes and Wilson disease. As both disorders are characterised 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.

Abbreviations: A-domain, actuator domain; AIPP1, ATPase interacting PDZ protein 1; CCS, copper chaperone for superoxide dismutase 1; CT, copper toxicosis in Bedlington terriers; CTR1, copper transporter 1; ER, endoplasmic reticulum; ETIC, endemic Tyrolean infantile cirrhosis; ICC, Indian childhood cirrhosis; ICT, idiopathic copper toxicosis; LEC, Long–Evans cinnamon; MBS, metal-binding site; MD, Menkes disease; N-domain, nucleotide-binding domain; NF, nuclear factor; OHS, occipital horn syndrome; OMIM, Online Mendelian Inheritance in Man; P-domain, phosphorylation domain; PLZF, promyelocytic leukemia zinc finger protein; SOD1, superoxide dismutase 1; TGN, trans-Golgi network; WD, Wilson disease

Keywords: copper; Menkes disease; ATP7A; Wilson disease; ATP7B

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