Wilson's disease - disorder of copper metabolism

Wilson's disease is a genetic disorder of copper metabolism in which copper accumulates in organs, especially the liver and brain, and leads to jaundice, cirrhosis and mental retardation. It is caused by a deficiency of ceruloplasmin, a copper-transporting enzyme. Two genes whose action should be in balance - ATP7A for absorption and ATP7B for excretion – play an important role in copper management. If either of these genes is mutated, the balance is disturbed, leading to the onset of a often fatal disease associated with either copper deficiency (Menkes disease) or accumulation in the body (Wilson disease).

A mutation causing Wilson's disease has been identified in a Labrador retriever. It is a missense mutation c.4151G>A in the ATP7B gene. However, the same mutation appears to be a common variant and segregates in many dog breeds, including those in which no increased prevalence has been reported. For example, in the Bedlington terrier or King Charles Cavalier Spaniel, this variant plays a role in copper toxicosis and contributes to copper accumulation in the liver, but it is not an isolated causative mutation. The association of this mutation with increased copper levels in the liver and the development of hepatitis has also been identified in Dobermans and Black Russian Terriers.

The mode of inheritance of the mutation is autosomal recessive. This means that only individuals who inherit the mutated gene from both parents will develop the disease. Carriers of the mutated gene are clinically healthy but pass the mutation on to their offspring. In the case of a mating between two heterozygous individuals, theoretically 25% of the offspring will be completely healthy, 50% of the offspring will be carriers and 25% of the offspring will inherit the mutated gene from both parents and will therefore be affected by the disease.

The genetic test can clearly reveal the genotype of the animal and is a useful tool for breeders to prevent unintentional breeding of affected puppies.

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References:

Fieten, H., Gill, Y., Martin, A.J., Concilli, M., Dirksen, K., van Steenbeek, F.G., Spee, B., van den Ingh, T.S., Martens, E.C., Festa, P., Chesi, G., van de Sluis, B., Houwen, R.H., Watson, A.L., Aulchenko, Y.S., Hodgkinson, V.L., Zhu, S., Petris, M.J., Polishchuk, R.S., Leegwater, P.A., Rothuizen, J. : The Menkes and Wilson disease genes counteract in copper toxicosis in Labrador retrievers: a new canine model for copper-metabolism disorders. Dis Model Mech 9:25-38, 2016. Pubmed reference: 26747866