Genetic basis of Cystinuria Type 3 - also known as the Bulldog-type risk factor, involves mutations primarily in the SLC3A1 gene and also in SLC7A9. In Bulldogs, French Bulldogs, and Mastiffs, two specific SLC3A1 mutations—c.574A>G (causing p.Ile192Val in exon 2) and c.2092A>G (p.Ser698Gly in exon 10)—are consistently linked to this type. Additionally, the SLC7A9 gene mutation c.649G>A is implicated but is not detected by some commercial Type 3 genetic tests. These mutations result in dysfunctional cystine transport proteins that impair kidney reabsorption of cystine, leading to excess cystine in urine. The inheritance of the SLC3A1 mutations behaves primarily as autosomal recessive, requiring two copies of mutant alleles for disease expression.
Pathophysiology - The mutated rBAT protein (encoded by SLC3A1) combined with the mutated b0,+ amino acid transporter subunit (encoded by SLC7A9) form a non-functional transporter complex in renal tubular cells. This complex defect reduces cystine reabsorption from urine, allowing cystine to accumulate and precipitate as crystals, forming uroliths (stones) in the urinary tract. Cystine stones can cause recurrent urinary obstruction and chronic urinary tract problems.
Complications - Affected dogs develop cystine urolithiasis with possible symptoms including difficulty urinating, hematuria, pain, and urinary obstruction. Repeated obstruction may cause urinary tract infections and kidney damage if untreated. The disease significantly impacts quality of life due to recurrent urinary issues and pain, sometimes requiring repeated medical or surgical interventions.
Why This Matters to Breeders and Vets - Bulldogs and related breeds show a high prevalence of these mutations, with some populations having up to 40% carrier frequency, leading to a substantial risk of cystinuria in the breed. Genetic testing for these known mutations helps breeders identify carriers and avoid breeding two carriers, which drastically reduces the incidence of cystinuria in offspring. Veterinarians can use this knowledge for early diagnosis, clinical management, and owner education on the disease prognosis and breeding implications.