Normal copper levels within the body are maintained by balancing the rates of copper absorption from the diet and copper excretion through the biliary system (or system that produces and transport the fluid used to break down fats into fatty acids). The balance that is maintained by physiological processes is known as homeostasis. Two proteins, ATP7A for absorption and ATP7B for excretion, act concurrently to maintain appropriate levels of copper. Variants in either of these genes may lead to early-onset, progressive and often-fatal diseases associated with copper deficiency (Menkes) or accumulation (Wilson) in the body. But, combinations of the identified variants in both genes have a neutralizing effect on copper level changes.
The P-type copper-transporting ATPases ATP7A and ATP7B have opposite but crucial roles for copper homeostasis. ATP7A is expressed in intestinal cells, where it is involved in copper absorption and delivery to the liver, where it is stored; ATP7B is expressed in the liver and is involved is excreting excess copper into the bile.
Variants in the ATP7A gene (located on the X chromosome) result in an early-onset and fatal copper-deficiency disorder known as Menkes disease, characterized by brain and cerebellar degeneration, failure to thrive, coarse hair and connective tissue abnormalities. In Labrador Retrievers, Menkes disease is caused by a single nucleotide substitution in the ATP7A gene (c.980C>T) that results in an amino acid substitution from a threonine to an isoleucine at position 327 of the ATP7A protein (p.Thr327Ile).
Wilson disease results from variants in ATP7B, and is associated with copper accumulation in the liver and secondarily in the brain, resulting in hepatic cirrhosis and neuronal degeneration. Age of onset is variable, and disease severity is associated with copper intake levels in the diet. In Labrador Retrievers, Wilson disease is caused by a single nucleotide substitution in the ATP7B gene (c.4358G>A) that causes an amino acid substitution in the C-terminus of the ATP7B protein (p.Arg1453Gln).
Therefore, in Labrador Retrievers, hepatic copper levels depend on the genotypes for both genes. The ATP7B variant leads to increased hepatic copper levels in an additive way. Copper levels are significantly higher in individuals homozygous for the mutation than in heterozygotes, which in turn have higher levels than individuals with no copies of the variant. Presence of both the ATP7A and ATP7B variants leads to an attenuation of copper accumulation, which appears to be more notable in males.
In Doberman Pinschers, a strong association between excess hepatic copper levels and the ATP7B (c.4358G>A) variant was identified. However, while the ATP7A variant was detected in the Doberman Pinscher study cohort, the sample set did not contain sufficient individuals with ATP7A to conclusively determine the interaction with ATP7B. Therefore, more work is needed to understand the interaction of these loci and any dog testing positive for ATP7A or ATP7B should be clinically evaluated.
Similarly, the ATP7B (c.4358G>A) variant has been detected in Black Russian Terriers with elevated hepatic copper levels. This research is ongoing.
The VGL offers a DNA test for the ATP7A and ATP7B variants. Test results help breeders make informed breeding decisions, as well as identify dogs to be clinically evaluated to determine copper levels and to manage dietary copper intake of their animals based on their combined genotypes for these two genes. For dogs with either of the variants, veterinarian consultation is recommended to best manage your dog’s health.
Note: This test is specific for the ATP7A and ATP7B copper toxicosis associated variants present in the Labrador Retriever. The ATP7B variant is also relevant in the Doberman Pinscher and Black Russian Terrier breeds but the role of ATP7A needs further evaluation in the both breeds. This assay does not detect copper- associated liver diseases in the Bedlington Terrier, Dalmatian, West Highland White Terrier, Keeshond, and German Shepherd.