Genetic basis of Cystinuria Type 3 - in Bulldogs, French Bulldogs, and Mastiffs involves multiple mutations mainly in the SLC3A1 and SLC7A9 genes. Key mutations in SLC3A1 include c.574A>G (p.Ile192Val) in exon 2 and c.2092A>G (p.Ser698Gly) in exon 10. A mutation in SLC7A9, c.649G>A, is also linked but is not detected by some commercial Type 3 genetic tests. These mutations impair the function of the cystine transporter complex responsible for renal reabsorption of cystine. Inheritance is primarily autosomal recessive; dogs with two mutated copies typically exhibit disease, while carriers are generally unaffected but can transmit the mutation.
Pathophysiology - The cystine transporter complex formed by proteins from SLC3A1 (rBAT) and SLC7A9 is dysfunctional due to these mutations. Impaired transporter function causes excess cystine in urine, which is poorly soluble and forms crystals that aggregate into urinary stones (uroliths). These stones can block the urinary tract, lead to pain, infections, and potentially kidney damage.
Complications - Affected dogs often suffer from cystine urolithiasis, causing symptoms like difficulty urinating, blood in urine, and frequent urination. Urinary obstruction from stones can cause severe pain and require medical or surgical intervention. Chronic issues may include recurrent urinary tract infections and long-term kidney damage if untreated.
Why This Matters to Breeders and Vets - Bulldogs and related breeds have a high frequency of these mutations, with a significant portion of the population being carriers or affected. Genetic testing helps breeders avoid mating two carriers, reducing the incidence of cystinuria in offspring. Vets rely on this knowledge for early diagnosis and to guide treatment and management of affected dogs.