OMIA 001135-9615 : Renal dysplasia in Canis lupus familiaris

In other species: horse , cattle

Possibly relevant human trait(s) and/or gene(s) (MIM number): 248250

Mendelian trait/disorder: unknown

Considered a defect: yes

Key variant is published: no

Inheritance: From a segregation analysis, Bovee (2003) concluded that the inheritance of this disorder is autosomal dominant with incomplete penetrance in the Shih Tzu breed.

Genetic testing: A DNA test for this disorder in a wide range of breeds is included in the OFA's list at http://www.offa.org/dna_alltest.html, which directs enquiries to DOGenes in Peterborough, Ontario, Canada (http://www.dogenes.com/), where a Renal Dysplasia Information Page states that this company has identified "the causative mutation" that is the basis of the DNA test. As indicated on the DOGenes website, the basis for this claim are the results of Whiteley et al. (2011), who reported an association between the disorder (variously defined) and the presence of one or more of three mutant alleles of the COX-2 gene (officially known as PTGS2, which encodes prostaglandin-endoperoxide synthase 2; also known as prostaglandin G/H synthase or cyclooxygenase). The three alleles are characterised by small insertions or deletions a short distance upstream of the translation initiation codon of the gene.

Unfortunately, the results presented by Whiteley et al. (2011) do not appear to justify the conclusions drawn: the criteria for "affected" were not defined sufficiently for any other researcher to conduct a comparable study; association analyses were conducted on family data while ignoring the family structure; the analyses were conducted on combined genotype data for whatever mutant alleles happened to exist in the available dogs, without any attempt to conduct separate analyses for individual mutant alleles; no segregation analysis was undertaken of the family data to provide insights into the form of inheritance of the disorder; and an across-breed analysis that involved only affected dogs (determined in a number of different manners, many not fully explained) led to the following conclusions, which speak for themselves: "No dogs affected with renal dysplasia were identified with a homozygous wild type genotype. Therefore these allelic variants in the canine Cox-2 gene are associated with this disease in these breeds. . . . These alleles were shown to have 100% correlation with clinical cases of RD in 19 breeds". Finally, it is not easy to reconcile these results with the single "causative mutation" claimed on the DOGenes website. Consistent with the concerns just listed, the editors of the journal in which the paper by Whitely et al. (2011) was published have themselves published an "Expression of Concern in order to make readers aware of the concerns about the reliability of the results and conclusions reported in the article" (PLOS ONE Editors, 2012)

The effects of the above alleles on methylation of the PTGS2 (COX-2) promoter in 13 dogs from 9 breeds were reported by Whiteley (2014). Eight of these dogs had biopsy (clinical) results: each of the five biopsy+ dogs come from a different breed, and two of the three biopsy- dogs have nothing but mutant alleles. Whiteley (2014) reported that "The allelic variants were associated with hypermethylation of the Cox-2 promoter only in clinical cases of RD. The wild-type allele was never methylated, even in clinical cases that were heterozygous for a mutant allele. In cases that were biopsy-negative, the promoter remained unmethylated, regardless of the genotype." Homozygosity for a mutant allele or heterozygosity for two mutant alleles does not necessarily indicate that a dog is affected.

Safra et al. (2015) reinforced the above doubts about the utility of the DNA test: they "evaluated sequences [corresponding to those used in the DNA test] from dogs free of renal disease, and from gray wolves; the dog’s direct wild ancestor . . . . [Their] findings suggest that regional variants [the ones used in the DNA test] are a common finding in dogs and do not present a genetic risk for RD."

Breed: Shih-Tzu.

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2015 Safra, N., Hayward, L.J., Aguilar, M., Sacks, B.N., Westropp, J.L., Mohr, F.C., Mellersh, C.S., Bannasch, D.L. :
DNA Sequence Variants in the Five Prime Untranslated Region of the Cyclooxygenase-2 Gene Are Commonly Found in Healthy Dogs and Gray Wolves. PLoS One 10:e0133127, 2015. Pubmed reference: 26244515. DOI: 10.1371/journal.pone.0133127.
2014 Whiteley, M.H. :
Allelic variation in the canine Cox-2 promoter causes hypermethylation of the canine Cox-2 promoter in clinical cases of renal dysplasia. Clin Epigenetics 6:7, 2014. Pubmed reference: 24708682. DOI: 10.1186/1868-7083-6-7.
2012 PLOS ONE Editors :
Expression of concern: Novel allelic variants in the canine cyclooxgenase-2 (Cox-2) promoter are associated with renal dysplasia in dogs. PLoS One 7:e49703, 2012. Pubmed reference: 23145184. DOI: 10.1371/journal.pone.0049703.
2011 Whiteley, MH., Bell, JS., Rothman, DA. :
Novel allelic variants in the canine cyclooxgenase-2 (Cox-2) promoter are associated with renal dysplasia in dogs. PLoS One 6:e16684, 2011. Pubmed reference: 21346820. DOI: 10.1371/journal.pone.0016684.
2010 Bruder, MC., Shoieb, AM., Shirai, N., Boucher, GG., Brodie, TA. :
Renal dysplasia in Beagle dogs: four cases. Toxicol Pathol 38:1051-7, 2010. Pubmed reference: 20884818. DOI: 10.1177/0192623310382558.
Seiler, GS., Rhodes, J., Cianciolo, R., Casal, ML. :
Ultrasonographic findings in Cairn Terriers with preclinical renal dysplasia. Vet Radiol Ultrasound 51:453-7, 2010. Pubmed reference: 20806879.
2003 Bovee, K.C. :
Renal dysplasia in Shih Tzu dogs. Proceedings of the 28th Congress of the World Small Animal Veterinary Association :http://www.vin.com/proceedings/Proceedings.plx?CID=WSAVA2003&PID=6602&O=Generic, 2003.
2001 Ohara, K., Kobayashi, Y., Tsuchiya, N., Furuoka, H., Matsui, T. :
Renal dysplasia in a Shih Tzu dog in Japan. J Vet Med Sci 63:1127-30, 2001. Pubmed reference: 11714030.
2000 Hoppe, A., Karlstam, E. :
Renal dysplasia in boxers and Finnish harriers Journal of Small Animal Practice 41:422-426, 2000. Pubmed reference: 11023130.
1999 Olenick, C.L. :
Congenital renal dysplasia and psychogenic polydipsia in a Bernese mountain dog Canadian Veterinary Journal - Revue Veterinaire Canadienne 40:425-426, 1999.
1998 Schulze, C., Meyer, H.P., Blok, A.L., Schipper, K., van, den, Ingh, T.S.G.A.M. :
Renal dysplasia in three young adult Dutch kooiker dogs Veterinary Quarterly 20:146-148, 1998. Pubmed reference: 9810631.
1997 Felkai, C., Voros, K., Vrabely, T., Vetesi, F., Karsai, F., Papp, L. :
Ultrasonographic findings of renal dysplasia in Cocker Spaniels - eight cases Acta Veterinaria Hungarica 45:397-408, 1997. Pubmed reference: 9557317.
Gross, T.L. :
Calcinosis circumscripta and renal dysplasia in a dog Veterinary Dermatology 8:27-31, 1997.
Miyamoto, T., Wakizaka, S., Matsuyama, S., Baba, E., Ohashi, F., Kuwamura, M., Yamate, J., Kotani, T. :
A control of a Golden Retriever with renal dysplasia Journal of Veterinary Medical Science 59:939-942, 1997. Pubmed reference: 9362046.
1996 Lobetti, R.G., Pearson, J., Jimenez, M. :
Renal dysplasia in a Rhodesian Ridgeback dog Journal of Small Animal Practice 37:552-555, 1996. Pubmed reference: 8934429.
1995 Kerlin, R.L., Vanwinkle, T.J. :
Renal dysplasia in Golden Retrievers Veterinary Pathology 32:327-329, 1995. Pubmed reference: 7604504.
1989 Murphy, M.G. :
Renal Dysplasia in a Cavalier King Charles Spaniel Irish Veterinary Journal 42:96-97, 1989.

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  • Created by Frank Nicholas on 15 Jul 2011
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