Copper homeostasis is (among other factors) regulated by the uptake of copper in the small intestine and the excretion of surplus copper via the biliary tract. In the breeds Labrador Retriever and Dobermann, dogs with copper toxicosis have a decreased ability to excrete copper resulting in excessive copper storage in the liver and other organs, leading to liver damage and cirrhosis. The disease is known to have a relatively late onset (middle aged or older dogs) with variable symptoms like weight loss, lethargy, weakness, vomiting, diarrhea, abdominal pain and neurological dysfunction.
A variant in the gene of the copper-transporting ATPase ATP7B is associated with an increased hepatic copper level and is inherited in an autosomal dominant mode with incomplete penetrance. This means that dogs with one copy of the variant (N/ATP7B) have an increased risk for developing copper toxicosis while dogs with two copies (ATP7B/ATP7B) have an even higher risk for the disease. Since there are multiple genetic and environmental factors causing copper toxicosis in dogs, a dog without any ATP7B variant is not excluded to suffer from copper toxicosis and there are also dogs with two copies of the ATP7B variant that do not show symptoms of copper toxicosis during lifetime. Dogs inheriting the ATP7B variant are recommended to be mated with dogs without any ATP7B variant.
A variant in the ATP7A gene (copper toxicosis modifier) is known to decrease the risk for copper toxicosis in Labrador Retrievers with one or two copies of the ATP7B variant by minimalizing the excessive accumulation of copper in the liver. Since this variant is inherited in an X-linked incomplete dominant manner, female dogs with one ATP7A (protective) variant and one normal (non-protective) ATP7A allele have a higher risk for copper toxicosis than male dogs which only need to inherit one copy of the (protective) ATP7A variant. This is the reason why female dogs are more commonly diagnosed with the disease than male dogs. In Dobermanns, the ATP7A variant has been identified, too, but until now, there is no relationship proven between the ATP7A variant and hepatic copper concentrations in this breed.