Abstract
Wilson’s disease (WD), also known as hepatolenticular degeneration, is an autosomal recessive inherited disorder resulting from abnormal copper metabolism. Reduced copper excretion causes an excessive deposition of the copper in many organs such as the liver, central nervous system (CNS), cornea, kidney, joints, and cardiac muscle where the physiological functions of the affected organs are impaired. The underlying molecular mechanisms for WD have been extensively studied. It is now believed that a defect in P-type adenosine triphosphatase (ATP7B), the gene encoding the copper transporting P-type ATPase, is responsible for hepatic copper accumulation. Deposited copper in the liver produces toxic effects via modulating several molecular pathways. WD can be a lethal disease if left untreated. A better understanding of the molecular mechanisms causing the aberrant copper deposition and organ damage is the key to developing effective management approaches.
Highlights
Wilson’s disease (WD), known as hepatolenticular degeneration, is an autosomal recessive disorder resulting from abnormal copper metabolism, subsequently leading to the accumulative deposition of copper in the target organs and impairing the normal functions of the affected organs
P-type adenosine triphosphatase (ATP7B) plays a double role in liver: It participates in copper transportation to trans-Golgi network (TGN) where copper is incorporated into ceruloplasmin, and it is involved in the biliary excretion of copper
Binding of copper to Antioxidant protein 1 (Atox1) in cytosol and shifting to TGN where copper is incorporated into ceruloplasmin with the help of ATP7B is among the important processes of copper transport [35]
Summary
Wilson’s disease (WD), known as hepatolenticular degeneration, is an autosomal recessive disorder resulting from abnormal copper metabolism, subsequently leading to the accumulative deposition of copper in the target organs and impairing the normal functions of the affected organs. Mutation of the ATP7B gene is closely linked to the impairment of copper excretion, leading to abnormal deposition of copper in the target organs [7]. P-type ATPase (ATP7B) is a critical enzyme essential for copper transport. Several domains of this gene contribute to copper transport. It was recently suggested that MBDs are not an indispensable domain for copper transport, since mutation of the MBDs alone perturbs but does not completely suppress the trafficking of ATP7B [16,17]. It is not clear how the SEHPL motif influences the copper transport, correlation between the mutation of SEHPL motif and WD has been identified [14]. The P-domain contains a highly conserved sequence motif DKTGT which is critical for enzyme phosphorylation [24]. Mutations may occur at any position of the gene, and may cause the deposition of copper
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