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.

Copper Toxicosis Modifiers

In Labrador Retrievers, additional mutations have been identified that act as modifiers of copper toxicosis. These variants alone do not cause disease and have no clinical significance in healthy individuals. However, in dogs carrying the ATP7B mutation, they may slow the accumulation of copper and reduce the risk of liver cell damage.

The first modifier is the missense mutation c.19C>T in the RETN gene, which encodes the protein resistin, produced mainly in adipose and liver tissue. Resistin does not play a direct role in copper metabolism but may influence how the liver responds to copper overload.

Because this is a modifier, it cannot be strictly determined whether the mutation is inherited dominantly or recessively. The protective effect may appear even in heterozygous individuals, while in homozygotes it may be more pronounced.

The second modifier is the missense mutation c.980C>T in the ATP7A gene, which encodes the alpha subunit of the copper-transporting ATPase. This variant is inherited in an X-linked manner, meaning it is carried on the X chromosome. Males will always express the mutation, whereas females will be carriers, and clinical disease will appear only if they inherit the mutation from both parents.

By testing for mutations in ATP7B and the modifiers RETN and ATP7A, it is possible to detect the risk of excessive copper accumulation in the liver early and better assess the potential severity of the disease in an individual dog. For breeders, genetic testing is a valuable tool to plan suitable mating pairs and prevent the 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