VetGen - The leader in veterinary genetic disease research and genetic disease detection services for purebred animals

Breeds Serviced

  • Bedington Terrier

Copper Toxicosis (CT)

Canine copper toxicosis ("CT") is an autosomal recessive disorder of copper accumulation which results in severe liver disease in several dog breeds. Unless specific anti-copper treatment is instituted, most affected dogs die at three to seven years of age. CT is, in particular, a severe problem in Bedlington Terriers. The frequency of CT in Bedlingtons is significant enough to be a major health concern. Affected dogs may be definitively diagnosed by invasive liver biopsy, but this technique cannot identify CT carriers. Therefore, CT carriers continue to be bred, creating extreme difficulties for responsible Bedlington breeders and owners who wish to halt the perpetuation of the disease.

Initially a linked marker test was developed as an aid to breeders, and more recently a direct test was developed that identifies a type of mutation known as a deletion. This particular deletion eliminates a major section of a copper metabolism gene, Commd1. This deletion test identifies the overwhelming majority of disease causing alleles and should be the focus of most testing. Vetgen still includes the linked marker types along with deletion status in our test results because there is small fraction of Bedlingtons that have do not have this deletion, but still have CT. This indicates that there is an extremely rare second mutation that, for the time being, may be tracked only by using the linked markers. Further explanation may be found under that test description.

Combined Deletion and Marker Test Result Types

Result Type Deletion Marker Explanation
A

Not carrying the deletion

1,1

Extremely small risk of having inherited the unknown mutation responsible for “bad 1’s”. Breeding considered safe unless mating pair are from line(s) known to have clinically affected 1,1 animals. Very high probability this animal does not have the disease.

B

Not carrying the deletion

1,2

Extremely small risk of having inherited the unknown mutation responsible for “bad 1’s”. Breeding considered safe unless either parent is from a line known to have clinically affected 1,1 animals and that parent also contributes a “bad 1”. Cannot have the diseas

C

Carrying one copy of the deletion

1,2

Extremely small risk of having inherited the unknown mutation responsible for “bad 1’s”. Can produce affected offspring if mated to another animal with an identical result type or result types E or F.

NOTE: if result is a “bad 1” and research reveals in the future that  the mutation is also from the same gene as the “bad 2” deletion, then this result would indicate an affected animal as opposed to a carrier.

D

Not carrying the deletion

2,2

Cannot have the disease, will not produce affected offspring. Thus is the optimal breeding choice.

E

Carrying one copy of the deletion

2,2

Cannot have the disease but can produce affected offspring if mated to another animal with an identical result type or result types C or F.

F

Carrying two copies of the deletion

2,2

Is affected with the disease but may or may not exhibit symptoms. Can produce affected offspring if mated to another animal with an identical result type or result types C or E.

CT Deletion Test

The discovery of a deletion in the Commd1 gene provided the basis for a direct test for the likely major cause of CT in Bedlington Terriers. This mutation was identified independently my multiple research groups and verified by others. The Commd1 gene encompasses a region of canine chromosome that also includes the previously available linked marker test. Information on the correlation of the deletion test and the marker test can be found below, but the gist of the matter is as follows:

  • The deletion in Commd1 seems to be responsible for > 95% of CT in Bedlington Terriers.
  • All deletions are linked to a marker type 2, but not every marker 2 is linked to a deletion.
  • All dogs with two copies of deletion are affected, and all dogs with one copy are carriers, at least.

Occasional dogs with a 1,1 marker type are now known to have copper toxicosis, both in North America and Europe. The frequency of this is very low, probably less than 5%. In those lines where 1,1 or 1,2 affected dogs have been reported, the Commd1 deletion test by itself is insufficient to steer clear of the disease.

To validate the correlation that has been shown in Canada and Europe between CT and the Commd1 deletion, we tested 43 Bedlington Terriers of known CT status from the families used in the validation of the original Vetgen marker system. We also tested an additional 65 animals of unknown CT status.

The results are as follows:
n=normal allele    d=deleted allele

New dogs of unknown Ct status
1,1 1,2 2,2
n,n 7 9 1
n,d 0 39 5
d,d 0 0 4
48 of 65 2 marker alleles are associated with the deletion while 17 of 65 are associated with the normal allele.
Old dogs of known Ct status
1,1 1,2 2,2
n,n 6* 1 1
n,d 0 15 6
d,d 0 0 15**

36 of 44 2 marker alleles are associated with the deletion while 8 of 44 are associated with the normal allelle.

*
2 of these 6 are affected
**
All 15 of these are affected

Our earlier work identified 1,1 and 1,2 affected dogs in US, Canadian, and European pedigrees. We have now confirmed the findings of other labs that there are affected Bedlington Terriers that are 1,1 and n,n. Work is ongoing to find a test predictive of Ct on 1 marker chromosomes.

CT Marker Test

VetGen began by offering a genetic linkage test for Copper Toxicosis in Bedlington Terriers. This test used a linked marker, which we established that had two alleles, or marker types, called 1 and 2. Our first use of this test required submission of DNA samples from a pedigree (a set of related dogs) that included at least one affected dog, diagnosed by liver biopsy. It was therefore somewhat cumbersome. Not all clients had the right situation to even submit samples, and in over half the samples submitted, the marker was not sufficiently informative to provide useful information. However, the data collected was invaluable not only in helping many breeders, but in establishing the existence of strong genetic disequilibrium.

Genetic Disequilibrium Between Copper Toxicosis and the Linked Marker

What was found was that over 90% of dogs that were 1/1 marker type were homozygous normal (clear) and over 90% of dogs that were affected were 2/2 marker type. Obviously, most 1/2 dogs are carriers with the 2 allele usually associated with the CT (disease) allele.

VetGen Test Procedure - Marker Typing

The finding of such a strong genetic disequilibrium allows VetGen to offer improved service for CT - marker typing. Bedlington breeder/owners can submit a DNA sample on a single dog, and VetGen will type it. This information can then be used as indicated above. If the dog is a 1/1, it is 90% + likely that the dog is homozygous normal (clear). If the dog is a 2/2 it is 72% likely that the dog is affected (90%+ of affected dogs are 2/2, but 72% of 2/2 dogs are affected - 24% are carriers). If the dog is a 1/2, VetGen data indicate the dog has a 95% chance of being a carrier.

Recommendations Regarding Breeding

Prior to the availability of the deletion test, VetGen recommended that 1/1 and 1/2 dogs be chosen primarily for breeding, eliminating the type 2 associated with CT in subsequent generations. This was the most immediate way to reduce the prevalence of CT. Now, with the deletion test, dogs which are 2,2 and have no copies of the deletion, or in select cases one copy, may also be used for breeding. Breeders should continue to get liver biopsies in 1/1 dogs to be used for breeding for the near to intermediate future because it is currently the only way to reduce the small pocket of CT associated with the 1 allele. Eventually, VetGen hopes to have a second genetic marker which will be useful for this situation, but even in that event biopsy data will be necessary in the beginning to get linkage phase information.

Special Thanks

Special thanks to the helpful Bedlington Terrier breeders from around the country who assisted CT research, and the AKC Canine Health Foundation, Morris Animal Foundation, and Orthopedic Foundation for Animals for their financial support of canine genetic research at the University of Michigan and Michigan State University that led to the genetic test for copper toxicosis in Bedlington Terriers.