Page 21 - Copper-associated hepatitis in the Labrador retriever diagnosis, treatment and genetics

to the cysteine residues of the XIAP protein and is delivered to XIAP via CCS95 (Figure 1). The binding of copper results in a conformational change of XIAP that induces an increased intracellular degradation and impairs the ability to inhibit caspases, thus lowering the apoptotic threshold96. This phenomenon sheds new light on the pathogenesis of copper-associated hepatitis, which starts with copper accumulation followed by hepatocellular apoptosis. Oxidative stress induced by free copper may not be the only trigger, as has been the general belief, which may have implications for therapeutic interventions.
Ubiquitously expression of COMMD1 in a number of different cell types indicates a more pleiotropic function of COMMD1 than copper metabolism alone70. Indeed, COMMD1 was found to be involved in many different cellular processes, including sodium metabolism64;97; 98 and regulation of NFkB61; 99 and HIF1a mediated transcription68; 100; 101.
Upon identification of COMMD1 in the Bedlington terrier, many new functions of COMMD1 were discovered and more knowledge is gained into the function and regulation of this interesting protein. Although the complete function of COMMD1 in copper homeostasis is not completely resolved yet, recent data indicates that it at least plays a role in the functioning and stability of ATP7B. This may indicate that human Wilson disease and canine COMMD1 deficiency copper toxicosis partly share their disease mechanism through disturbance of ATP7B-mediated copper export from hepatocytes.
COMMD1 in human copper toxicosis
The non-Wilsonian forms of copper toxicosis ICC, ETIC and ICT resemble the hepatic form of Wilson disease, but in contrast there is no neurological involvement and the age of onset is often early in childhood (Table 1). In these diseases, consanguinity and high dietary copper intake are suggested to play a role in the pathogenesis31-33. Since a direct role of ATP7B mutations had been excluded and the phenotype of humans with ICC, ETIC, or ICT resembles that of BTCT, COMMD1 was tested as a candidate gene. In two small studies of 23 and 3 cases respectively, no correlation between mutations and phenotype could be established102; 103.
General introduction
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Chapter 1