Development of the JRD Test

Development of a DNA-Test for JRD
by Dr. Bernd Hackauf

More than 1000 inherited diseases have been described in dogs^[1,2] representing the major challenge of breeding purebreed dogs in the 21^st century. In a recently published review on inherited defects in pedigree dogs, which was primarily addressed to disorders related to breed standards, it has been reported, that each of the top 50 UK Kennel Club registered breeds was found to have at least one aspect of its conformation predisposing it to a disorder; and 84 disorders were either directly or indirectly associated with conformation^[3]. Molecular selection methods currently allow an efficient genetic management, however, only for a minor part of the known genetic defects in dogs.

A novel molecular assay has most recently been established addressing an important category of kidney diseases in dogs, Juvenile Nephropathy alias Juvenile Renal Dysplasia. Here, the state of the art of science and technology concerning the genetic management of this kidney disease by means of a molecular genetic approach, which provides an invaluable contribution to the combat against inherited diseases in dogs.

The dog genome encodes for more than 19.000 genes^[1]. One approach to extract from this tremendous amount of information exactly the particular gene sequence associated with the expression of a trait like a certain disease is to analyze candidate genes. A gene becomes a candidate in research, if there is knowledge e.g. from model organisms on the association of the gene with the expression of a trait like a certain disease.

This approach has now successfully been applied by the geneticist Dr. Mary Whiteley to detect the gene governing JRD in dogs^[9]. Most notably and beneficial for Dr. Whiteley's research was, that the mouse model displays a JRD phenotype identical with that observed in dogs. Sequence analysis of initially 6 candidate genes allowed Dr. Whiteley finally to identify the JRD associated mutation in the gene Cyclooxygenase-2 (COX-2) of Lhasa Apsos and Shih Tzus, respectively. Furthermore, genetic variants (alleles) of the COX-2 gene have been identified in other breeds like the English Cocker Spaniel, which are affected by JRD as well^[9]. In contrast, breeds which have yet not been reported to be affected by JRD revealed only the non-mutated wild type allele of COX-2. Based on these findings, Dr. Whiteley has established a DNA assay which allows to discriminate the different COX-2 alleles. This assay enables to genotype dogs at the COX-2 gene with high precision which, subsequently, allows to classify the genetic predisposition of a dog for JRD.

The COX-2 genotypes are scored analogous to prcd-PRA or FN , i.e. (A) clear: the dog carries no mutant COX-2 allele, (B) carrier: the dog carries one copy of a mutant COX-2 allele, (C) homozygous mutant genotype: the dog carries two copies of a mutant COX-2 allele. With results (B) and (C) the dog may be potentially affected by JRD and could pass the mutant allele on to its progeny^[5].

The results of this DNA assay should be carefully used for any breeding decisions, which largely depends on the frequency of mutant COX-2 alleles in a breeding population. In a North American Shih Tzu population, for instance, JRD occurs in high frequency. Among 74 randomly selected dogs only 16% revealed no histological symptoms of the disease^[7]. In populations like this a comprehensive selection of carriers would be the worthiest breeding decision, as it would sustainably narrow the gene pool. Matings between dogs clear of any detrimental mutation in this and other genes should be a long term goal. However, this goal can be reached by using the available DNA assay's together with cool-headed breeding decisions, which should be addressed mainly to breed and sell puppies not affected by a genetic inherited disorder and not to endanger a breed by an artificial reduction of genetic diversity.

NOW READ THE FULL ARTICLE: by Dr. Bernd Hackauf

http://www.cocker-springer.de/svshrjrd_gb.htm

References

[1] Ostrander EA, Wayne RK (2005) The canine genome. Genome Res. 15:1706-1716

[2] Sargan DR (2004) IDID: inherited diseases in dogs: web-based information for canine inherited disease genetics. Mamm Genome. 15:503-506

[3] Asher L, Diesel G, Summers JF, McGreevy PD, Collins LM. (2009) Inherited defects in pedigree dogs. Part 1: disorders related to breed standards. Vet J. 182:402-411.

[4] Krook L. (1957) The Pathology of Renal Cortical Hypoplasia in the Dog. Nord. Vet.-Med. 9, 161-176.

[5] http://www.dogenes.com/jrd.html

[6] Felkai C, Vörös K, Vrabély T, Vetési F, Karsai F, Papp L. (1997) Ultrasonographic findings of renal dysplasia in cocker spaniels: eight cases. Acta Vet Hung. 45:397-408.

[7] Bovee KC (2003) Renal Dysplasia in Shih Tzu Dogs. Proc. 28^th World Congress of the World small Animal Veterinary Association.

[8] Hoppe A, Swenson L, Jönsson L, Hedhammar A (1990) Progressive nephropathy due to renal dysplasia in shih tzu dogs in Sweden: A clinical pathological and genetic study. J. Small Animal Pract.31:83 – 91

[9] Whiteley M. H. (2009) Compositions and methods for detecting Juvenile Renal Dysplasia or oxalate stones in dogs. Intl. Patent WO/2009/092171, filed January 22, 2009, and issued July 30, 2009.

[10] Hackauf B. (2009) Rassehundezucht auf dem Prüfstand. 1: Eine genealogische Bestandsaufnahme. Der Jagdspaniel 2/09:33-41

[11] Hackauf B. (2009) Rassehundezucht auf dem Prüfstand. 2: Eine molekulargenetische Bestandsaufnahme. Der Jagdspaniel 3/09:17-20

[12] Leroy G, Verrier E, Meriaux JC, Rognon X (2009) Genetic diversity of dog breeds: within-breed diversity comparing genealogical and molecular data. Anim Genet. 40:323-332.