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

• Published in: Journal of medical genetics Vol. 44; no. 11; pp. 673 - 688
• Main Authors: de Bie, P, Muller, P, Wijmenga, C, Klomp, L W J
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01-11-2007; BMJ; BMJ Publishing Group LTD; BMJ Group
• Subjects: Adenosine Triphosphatases - chemistry; Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - physiology; Adenosine Triphosphate - metabolism; Animals; ATP7A; ATP7B; Biological and medical sciences; Cation Transport Proteins - chemistry; Cation Transport Proteins - genetics; Cation Transport Proteins - physiology; copper; Copper - metabolism; Copper-transporting ATPases; Defects; Disease; Disease Models, Animal; Enzymes; Female; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genetics of eukaryotes. Biological and molecular evolution; Genotype; Hepatolenticular Degeneration - genetics; Hepatolenticular Degeneration - metabolism; Humans; Laboratories; Male; Medical genetics; Medical sciences; Menkes disease; Menkes Kinky Hair Syndrome - genetics; Menkes Kinky Hair Syndrome - metabolism; Metabolic diseases; Metals (hemochromatosis...); Mice; Mice, Mutant Strains; Molecular and cellular biology; Mutation; Mutation, Missense; Other metabolic disorders; Phenotype; Protein Interaction Mapping; Protein Structure, Tertiary; Proteins; Rats; Rats, Inbred LEC; Respiration; Review; Rodents; Structure-Activity Relationship; Wilson disease; Zebrafish; Human; Skin disease; Nervous system diseases; Correlation; Wilson disease; Pathogenesis; Metabolic diseases; Enzymopathy; Inorganic element; Cerebral disorder; Genetic disease; Phenotype; Central nervous system disease; Digestive diseases; Genetics; Menkes syndrome; Mutation; Copper
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.2007.052746

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.