Predisposition test for the development of cystinuria in English bulldogs and French bulldogs

Cystinuria is a genetic disorder occurring in several animal species inclusive humans, cats and more than 60 canine breeds. The phenotypic and genetic expression of cystinuria is heterogeneous and that even among the individual dog breeds.  It is most common in English Bulldogs (the frequency of occurrence is 32 times higher than in other dog breeds) and in Newfoundland dogs and Dachshunds.

Cystinuria is a metabolic disorder caused by a defect in the transport of amino acids (cystine, ornitine, lysine and arginine) in the kidneys.

Dogs with cystinuria do not properly reabsorb cystine in the kidney tubules, causing the urine to contain abnormally high levels of cystine. Cystine is insoluble in urine and excess of urinary cystine results in formation of cystine crystals which in turn can lead to formation of cystine stones (uroliths) irritating the urinary tracts.  Dysuria symptoms – burning or pain during urination - have been observed. Affected dogs may be prone to urinary tract infections and are at risk for urinary blockage. The average age of the onset of clinical signs associated with the presence of cystine uroliths in urine is 15.6 months. Due to anatomic differences (the males have longer urethra than the females) the disease is more common in males. The cystinuria is a very uncomfortable disease and a surgery intervention is often inevitable.

In connection with cystinuria 3 mutations in SLC7A9 and SLC3A1 genes encoding for heterodimeric transporter of amino acids expressed in kidney proximal tubules have been discovered.  The mutation in one of these genes causes the defect in the transport of cystine  and the three dibasic amino acids arginine, lysine and ornithine from tubule lumens to the cells of proximal tubules which leads to their accumulation in the urine. Cystine is almost insoluble in acid solutions (urine is acidic) where it precipitates and may form cystine stones.

The mutations responsible for these problems in English Bulldocks and French Bulldocks are SLC3A1 c.574A>G (I192V) - exon 2, SLC3A1 c.2092A>G(S698G) - exon 10 and SLC7A9 c.649G>A. The SLC3A1 mutation shows autosomal recessive mode of inheritance. That means that cystinuria will develop in dogs that inherited two mutated alleles from both parents (recessive homozygous). Heterozygous dog inherited the mutated allele only from one of its parents and does not show any signs and is considered clinically healthy, but can pass the mutated allele to its offspring. The SLC7A9 mutation shows incomplete recessive inheritance i.e. even heterozygous dogs may develop symptoms of cystinuria.

Genetic tests offered by our laboratory have been developed to detect the presence of these mutations and may help the breeders to eliminate these undesirable disease genes in their breeds.

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Possible results of the genetic test:

A) Dogs carrying homozygous mutation in exone 2 and/or in exone 10 of SLC3A1 gene are at risk of cystinuria development, it means dogs with c.574G/G and/or c.2092G/G result. Cystinuria can also develope in dogs, that carry heterozygous mutation in SLC7A9 gene - incompletely recessive disorder, it means dogs with c.649G/A result. We recommend mating only with partners who do not carry any of these mutations (result D).

B) Carriers at risk of cystinuria development are heterozyous in one or more mentioned mutations and always carry c.649G/A, it means dogs with c.574A/G and/or c.2092A/G and always c.649G/A result. We recommend mating only with partners who do not carry any of these mutations (result D).

C) Carriers of cystinuria are heterozyous in one or two tested mutations of SLC3A1 gene, it means dogs with c.574A/G and/or c.2092A/G and c.649G/G result. We recommend mating only with partners who do not carry any of these mutations (result D).

D) Dogs with c.574A/A, c.2092A/A, c.649G/G result are out of risk of cystinuria development (i.e. these mutations dependent cystinuria).

The test does not exclude existence of another, nowadays unknown, mutation which can cause cystinuria.

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Reference:

Harnevik, L., Hoppe, A., Söderkvist, P.: SLC7A9 cDNA cloning and mutational analysis of SLC3A1 and SLC7A9 in canine cystinuria. Mamm Genome 17:769-76, 2006. Pubmed reference: 16845473.

Brons, A.K., Henthorn, P.S., Raj, K., Fitzgerald, C.A., Liu, J., Sewell, A.C., Giger, U.: SLC3A1 and SLC7A9 mutations in autosomal recessive or dominant canine cystinuria: a new classification system. J Vet Intern Med 27:1400-8, 2013. Pubmed reference: 24001348

B. Ruggerone, S. P. Marelli, P. Scarpa, M. Polli: Genetic evaluation of English bulldogs with cystine uroliths; August 13, 2016 | Veterinary Record