Quick Summary
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Phenotype: Copper toxicosis is an inherited metabolic disorder that can lead to liver failure when copper levels are higher than normal. The proper amount of copper is very important to normal metabolism and liver function. If there is a copper deficiency this is known as Menkes disease. On the other hand, when there is an accumulation of excess copper in the body it is referred to as Wilson disease and liver damage results.
Mode of Inheritance: Additive, Sex linked (ATP7A)
Alleles: N = normal, 7A = ATP7A Menkes variant, 7B = ATP7B Wilson variant
Breeds appropriate for testing: Labrador Retriever, Labrador Retriever crosses, and potentially Doberman Pinschers, Black Russian Terriers and Bedlington Terriers (specifically ATP7B)
Explanation of Results:
ATP7A in females:
- Female dogs with the N/N genotype do not have the ATP7A variant associated with Menkes disease in canines. Individuals with this genotype will not have altered hepatic copper levels due to this variant.
- Female dogs with the N/7A genotype have 1 copy of the ATP7A variant detected. The individual may have lower levels of hepatic copper. But this variant is likely not the only variant contributing to low levels of copper in dogs across breeds. Environmental factors including diet are thought to contribute to the variability in copper levels detected.
- Female dogs with the 7A/7A genotype have 2 copies of the ATP7A variant detected. The individual may have very low levels of hepatic copper, environmental factors are thought to contribute to the variability in copper levels detected.
ATP7A in males:
- Male dogs with an N genotype have no copies of the ATP7A variant. Individuals with this genotype will not have altered hepatic copper levels due to this variant.
- Male dogs with a 7A genotype have 1 copy of the ATP7A variant. The individual may have very low levels of hepatic copper, environmental factors are thought to contribute to the variability in copper levels detected.
ATP7A may only be relevant in the Labrador Retriever and related crosses.
ATP7B:
- Dogs with an N/N genotype have no copies of the ATP7B variant associated with Wilson disease in canines. Dogs with this genotype will not have altered hepatic copper levels due to this variant, however other yet unknown variants cannot be ruled out by this genetic test.
- Dogs with an N/7B genotype have 1 copy of the ATP7B variant. The individual may have moderately elevated levels of hepatic copper, environmental factors such as diet are thought to contribute to the variability in copper levels detected.
- Dogs with an 7B/7B genotype have 2 copies of the ATP7B variant. Individuals with this genotype may have significantly elevated hepatic copper levels and environmental factors are thought to contribute to the variability in copper levels detected.
ATP7A and ATP7B:
Dogs with variants in both genes ([N/7A, N/7B], [N/7A, 7B/7B], [7A/7A, N/7B], [7A/7A, 7B/7B], [7A, N/7B], [7A, 7B/7B]) appear to have varied hepatic copper levels depending upon the combination of alleles and other environmental contributing factors. However, data suggests affected alleles at both loci have a neutralizing effect on copper level changes and Labrador Retriever dogs with these genotypes will likely be unaffected. It is not yet known how the presence of 7A by itself or in combination with 7B impacts copper levels in the Doberman.
Results of this test can be submitted to the OFA (Orthopedic Foundation for Animals)
Labrador Retriever Health Panel 1
$165 per animal
Labrador Retriever Health Panel 2
$180 per animal
Sample Collection
Dog DNA tests are carried out using cells brushed from your dog's cheeks and gums. The preferred cytology brushes are sent to you by mail, or you may provide your own brushes. For accepted alternative brushes, click here
We recommend waiting until puppies are at least three weeks old before testing.
Step-By-Step:
- Make sure the dog has not had anything to eat or drink for at least 1 hour prior to collecting sample.
- When swabbing puppies, isolate each puppy from the mother, littermates and any shared toys for 1 hour prior to swabbing. Puppies should not have nursed or eaten for 1 hour prior to collecting sample.
- If collecting samples from more than one dog, make sure to sample one dog at a time and wash your hands before swabbing another dog.
- Label brush sleeve with name or ID of dog to be sampled.
- Open brush sleeve by arrow and remove one brush by its handle.
- Place bristle head between the dog’s gums and cheek and press lightly on the outside of the cheek while rubbing or rotating the brush back and forth for 15 seconds.
- Wave the brush in the air for 20 seconds to air dry.
- Insert brush back into sleeve.
- Repeat steps 5 - 8 for each unused brush in sleeve on a fresh area of cheek and gums. Make sure to use and return all brushes sent by the VGL. In most cases, it will be 3 brushes per dog. If using interdental gum brushes, please note that the VGL requires 4 brushes per dog and only moderate or wide interdental gum brushes are accepted.
- Do not seal brushes in sleeve.
- Place all samples in an envelope and return to the address provided.
ATTENTION:
- Do not collect saliva/drool – the key to obtaining a good sample is getting cheek cells on the swab
- Do not rub swab on the dog’s tongue or teeth – this will result in poor quality sample
- Do not collect a sample from a puppy that has recently nursed – the mother’s genetic material can rub off on the puppy’s mouth and contaminate the sample
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.
A 2023 publication reported the presence of the ATP7B (c.4358G>A) variant in Bedlington Terriers affected by copper toxicosis. Copper toxicosis in the Bedlington Terrier had been previously associated with a deletion in the COMMD1 gene. The recent study identified copper toxicosis-affected Bedlington Terriers that had 2 copies of the ATP7B variant and no copies of the COMMD1 deletion. The frequency of the ATP7B variant was significantly higher in affected Bedlington Terriers compared to controls, indicating this ATP7B variant is also associated with copper toxicosis in the breed. However, some Bedlington Terries that were homozygous for the ATP7B variant had normal copper levels.
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, Black Russian Terrier and Bedlington 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 Dalmatian, West Highland White Terrier, Keeshond, and German Shepherd.
