Page 27 - Copper-associated hepatitis in the Labrador retriever diagnosis, treatment and genetics

General introduction
influences, or an increased stress on the liver during pregnancy and lactation may influence deterioration of the liver function, however, no evidence for this hypothesis currently exists. Copper accumulating traits in the Labrador retriever show a heritability of up to 85 percent137. Involvement of environmental factors in the disease pathogenesis was proven by the fact that dietary management with a low copper diet was effective to prevent progression of the disease138. Unpublished results demonstrated that the disease is polygenic and the Labrador form of copper storage disease might become a good example of the power of canine populations to resolve complex genetic diseases.
Opportunities and pitfalls in genetic studies into canine copper storage disorders
Discovery of the COMMD1 gene in the Bedlington terrier was an enormous step forward in the diagnosis of affected and carrier dogs by use of a DNA test. The implementation of this test in selection of breeding dogs, led to dramatic decrease in the number of affected puppies that were born. In addition, the subsequent functional studies have shed a new light on the regulation of mammalian copper metabolism. However, several questions remain unanswered. A minority of Bedlington terriers are affected with copper toxicosis, but do not have the homozygous COMMD1 exon 2 deletion. In addition, the role of COMMD1 as a modifier gene in Wilson disease was not clearly established and for non-Wilsonian forms of copper toxicosis, no causal mutations have been detected thus far. These phenomena are a reflection of the complex regulation of copper metabolism and it is likely that other, yet unidentified genes may be at play.
In the previous section we have summarized the forms of copper accumulation that are well documented in different dog breeds. The phenotypes in the dogs show resemblances with human copper storage disorders. For example, copper accumulation in the liver and response to D-penicillamine therapy are features that are both shared among all human and canine forms of copper toxicosis. The age of onset of clinical signs in dogs is comparable with the general age of onset in Wilson disease, namely in adolescence or middle age. In non-Wilsonian forms of copper toxicosis, a strong influence of dietary copper
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Chapter 1