Renal Disease
Renal Disease and the DNA Test for Renal Dysplasia
January, 2022
Renal (kidney) disease in dogs has numerous causes. Young dogs with renal failure may have an inherited condition, or the problem may be caused by infection (such as Herpes virus infection before birth) or toxins, ex. melamine in dog food [1]. Familial renal diseases have been reported in many breeds, but have not been well documented in Shetland Sheepdogs. Nonetheless, it is reasonable to assume that familial renal disease may affect Shelties, as various types have been reported in numerous breeds. Reports of renal disease in young (less than 8 yrs. of age) Shelties by breeders and dog owners have been received by the American Shetland Sheepdog Association’s Research Advisory Committee (RAC).
Renal dysplasia (RD) is a cause of inherited kidney disease in dogs. According to Dr. George Lees, a veterinary expert concerning hereditary renal disease in dogs and cats, RD is a sporadic problem that likely occurs in all breeds. Its appearance may or may not be due to an inherited cause. Dr. Lees has also stated that RD is difficult to diagnose as there is no clear agreement between pathologists on what constitutes RD. The routine microscopic evaluation of biopsy specimens may not be sufficient to adequately characterize many renal diseases, and although ultrasound evaluation can detect abnormal renal changes, it is not specific or definitive for renal dysplasia. Ultrastructural examination of tissue via electron microscopy may be necessary [2].
DOGenes, Inc. [3] offers a DNA test for renal dysplasia in several dog breeds including Shelties. This test detects variants in the Cox-2 gene that are claimed to be associated with RD [4]. Defects in Cox-2 do cause renal dysplasia in mice. In dog breeds in which it has been investigated, this particular form of RD appears to be inherited as a dominant trait with incomplete penetrance, that is, only one copy of the defective gene is needed for a dog to be affected, but many unaffected dogs can carry one or even two variant copies of the gene. According to the DOGenes website, the risk associated with the variants is in the range of 3-5%. In other words, 95-97% of dogs harboring these variants are normal. In 2014, Dr. Whiteley hypothesized that these variant genes are susceptible to chemical modification that silences them, resulting in RD; and that the variant genes in unaffected dogs are not silenced [5]. The Cox-2 protein is not altered by the gene variant, but the variant gene may or may not express the protein, depending on whether the gene itself is chemically modified. Data from a limited number of dogs so far support her hypothesis.
After careful consideration, the RAC urges caution in the use of the test at this time. The results of the research on which the DNA test is based are suggestive of a cause and effect, but are based on a limited number of individuals, raising the question of whether the correlation will hold up if more individuals are investigated. Even if it does, there is reason for caution. The mutations mentioned in the DOGenes test occur at extremely high frequencies in some breeds of dogs [4] and, as stated earlier, many individuals harbor these variants with no apparent ill effects. For Shelties, fewer than half would be expected to test “clear,” and the vast majority of “mutant” dogs are not likely to be clinically affected; yet, if the mutants are indeed causative, then even “carriers” could be affected. Finally, as the DOGenes website notes, other mutations are also known to cause kidney disease. We realize that it is devastating to have a pup with renal disease, but for the reasons given above, the RAC does not presently endorse using the DOGenes DNA test to guide a breeding program. Because of the potential for damage to the genetic diversity of the breed, dogs carrying common mutations should not be eliminated from breeding lines unless the mutation is strongly associated with disease [7].
In order to determine whether or not genetically predisposed renal disease exists in Shelties, information from Shelties with renal failure must be collected and evaluated. The ASSA and the ASSA Foundation are supporting research to characterize kidney disease in Shelties. This study may take several years to yield results, but is necessary to confirm and characterize hereditary renal disease that might exist in our breed.
The AKC has an informational section about kidney disease on its website at: http://www.akc.org/learn/akc-gazette/kidney-disease/ .
References:
[1] Personal communication. Dr. George Lees, Professor of Small Animal Medicine & Surgery at the College of Veterinary Medicine, Texas A & M University, Director of the Texas Veterinary Renal Pathology Service at Texas A&M University, participant in “The International Veterinary Renal Pathology Initiative and Standardization Project” under the auspices of the World Small Animal Veterinary Association.
[2] Recognition of the need to develop a more standardized classification scheme for renal diseases has led to the formation of The International Veterinary Renal Pathology Initiative and Standardization Project(https://wsava.org/Committees/renal-standardization-project/ ).
[4] Whiteley MH, Bell JS, Rothman DA. Novel Allelic Variants in the Canine Cyclooxgenase-2 (Cox-2) Promoter Are Associated with Renal Dysplasia in Dogs. PlosOne 7:e16684. 2011.
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0016684#s5
[5] Whiteley MH. Allelic variation in the canine Cox-2 promoter causes hypermethylation of the canine Cox-2 promoter in clinical cases of renal dysplasia: Clin Epigenetics, 2014; 6(1): 7. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234983/
[6] Mellersh C. DNA testing and domestic dogs. Mamm Genome, 2012; 23:109-123. DOI 10.1007/s00335-011-9365-z, http://link.springer.com/article/10.1007%2Fs00335-011-9365-z?LI=true