Volume 142, Issue 4, Pages 692-696 (April 2012) Defining Wilson Disease Phenotypes: From the Patient to the Bench and Back Again  Peter Ferenci  Gastroenterology  Volume 142, Issue 4, Pages 692-696 (April 2012) DOI: 10.1053/j.gastro.2012.02.035 Copyright © 2012 AGA Institute Terms and Conditions

Figure 1 Schematic depicting effects of phenotypic defects in the Wilson ATPase. Copper (red circle) is taken up from albumin and other carriers in blood by the copper transporter CTR1. In the hepatocyte, copper is stored bound to metallothionein or distributed to specific sites via copper chaperones (only ATOX1 shown). Under basal conditions, the Wilson ATPase (orange cylinder with arrow) is located in the trans-Golgi network (TGN), where it receives copper from the copper chaperone ATOX1 (green nicked-diamond). Copper transfer to the transmembrane domain is accompanied by ATP hydrolysis and formation of transiently phosphorylated intermediates of the Wilson ATPase (‘phosphorylation’). At low copper concentrations, the Wilson ATPase participates in the mechanism for incorporating copper into apoceruloplasmin (blue collar) to generate holoceruloplasmin (blue collar plus Cu), but at high copper concentrations it expedites biliary excretion of copper. Structural phenotypic defects include (1) absence of any intact Wilson ATPase, (2) misfolding of Wilson ATPase leading to its retention in the endoplasmic reticulum, (3) failure to bind to ATOX1 (not shown), and (4) ineffective interaction with other proteins, which directs the intracellular movement of the Wilson ATPase (not shown). Functional phenotypic defects include (1) abnormal phosphorylation or copper transfer and (2) disruption of intracellular copper trafficking (not shown). Functional phenotypic defects may be as severe as absence of Wilson ATPase. Either type of phenotypic defect can result in copper accumulation and toxicity in hepatocytes. BC, bile canaliculus; Mt, metallothionein; RER, rough endoplasmic reticulum; SER, smooth endoplasmic reticulum; TGN, trans-Golgi network. Gastroenterology 2012 142, 692-696DOI: (10.1053/j.gastro.2012.02.035) Copyright © 2012 AGA Institute Terms and Conditions