Copper Toxicosis (Menkes and Wilson diseases)

Quick Summary

Copper toxicosis is a metabolic disorder that can cause chronic liver failure and neurological problems that result from deviations in normal levels of copper in the body.

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

Alleles: N = normal, 7A = ATP7A Menkes variant, 7B = ATP7B Wilson variant

Breeds appropriate for testing: Labrador Retriever, Labrador Retriever crosses, and potentially Doberman Pinschers and Black Russian 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)

 

Price

$50 one test per animal
$30 as additional test (same animal)

Panels Available
Additional Details

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.

Turnaround Time
At least 15 business days

Species

Dog

Type of Test

Results Reported As

ATP7A**

ATP7B

Female Results

N/N

N/N

No copies of the ATP7A and ATP7B variants.

N/7A

N/N

One copy of the ATP7A variant and may have decreased levels of hepatic copper.

7A/7A

N/N

Two copies of the ATP7A Variant and may have very low levels of hepatic copper.

N/N

N/7B

One copy of the ATP7B variant and may have increased levels of hepatic copper.

N/N

7B/7B

Two copies of the ATP7B variant and may have very high levels of hepatic copper.

N/7A

N/7B

One copy each of the ATP7A and ATP7B variants. Hepatic copper levels may be slightly elevated.

N/7A

7B/7B

One copy of the ATP7A variant and two copies of the ATP7B variant. Hepatic copper levels may be elevated.

7A/7A

N/7B

Two copies of the ATP7A variant and one copy of the ATP7B variant. Hepatic copper levels may be slightly decreased.

7A/7A

7B/7B

Two copies each of the ATP7A and ATP7B variants. Hepatic copper levels may be slightly altered from normal ranges.

ATP7A

ATP7B

Male Results

N

N/N

No copies of the ATP7A and ATP7B variants.

7A

N/N

The dog has the ATP7A variant and may have very low levels of hepatic copper.

N

N/7B

One copy of the ATP7B variant and may have increased levels of hepatic copper.

N

7B/7B

Two copies of the ATP7B variant and may have very high levels of hepatic copper.

7A

N/7B

The dog has the ATP7A variant and one ATP7B variant. Hepatic copper levels may be slightly altered from normal ranges.

7A

7B/7B

The dog has the ATP7A variant and two copies of the ATP7B variant. Hepatic copper levels may be elevated.

 

* Any dog testing positive for 7A, 7B or both should be clinically evaluated.
**ATP7A testing may only be relevant for the Labrador Retriever and related crosses

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. (2016) 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(1):25-38. PMID 26747866 DOI: 10.1242/dmm.020263 

Hoffmann, G., (2009) Copper-associated liver diseases. Vet Clin Small Animal 39 489-511. Liver Copper Storage Disease.

Wu, X., Mandigers, P.J.J., Watson, A.L., van den Ingh, T.S.G.A.M., Leegwater, P.A.J., Fieten, H. (2019) Association of the canine ATP7A and ATP7B with hepatic copper accumulation in Dobermann dogs. J Vet Intern Med 33:1646-1652, 2019. PMID: 31254371. DOI: 10.1111/jvim.15536.