Cystinuria Type I-A (SLC3A1 gene)

Cystinuria is a disorder caused by a defect in the reabsorption of certain amino acids in the proximal tubule of the nephron and the gastrointestinal epithelium. As a consequence of the accumulation of these amino acids, crystals and stones may form in the urinary tract.

Symptoms

Cystinuria is manifested by a number of symptoms, such as recurrent cystitis, hematuria and stranguria. In addition, this hereditary disease can lead to the formation of stones or crystals in the kidney, urinary bladder or urethra, which can result in partial or complete urinary obstruction. If not effectively treated, this obstruction can cause irreversible damage to the kidneys and lead to kidney failure.

Disease Management

There are different treatment options for cystinuria including surgical and non-surgical interventions. If the size of the stones is very small, urohydropropulsion is recommended, which consists of flushing the stones by using a specialized catheter. The ultrasonic dissolution method can also be chosen, which allows the stones to be broken up. If the stones are large and cannot be removed in any other way, surgical extraction is used. In order to avoid the recurrence of kidney stones, diets that favor the production of alkaline and more diluted urine are recommended.

Genetic basis

This disease follows an autosomal recessive mode of inheritance. Autosomal recessive inheritance means that the dog, regardless of sex, must receive two copies of the mutation or pathogenic variant to be at risk of developing the disease. Both parents of an affected dog must carry at least one copy of the mutation. Animals with only one copy of the mutation are not at increased risk of developing the disease, but may pass the mutation on to future generations. Breeding between dogs carrying genetic variants that can cause disease, even if they do not show symptoms, is not recommended.

Technical report

Cystinuria is caused by a defect in the transport of amino acids (cystine, ornithine, lysine and arginine) in the proximal tubule of the nephron and in the gastrointestinal epithelium. The transport of these amino acids occurs through a heteromeric transporter encoded by the SLC3A1 and SLC7A9 genes. Therefore, any mutation in these two genes that affects the functionality of the transporter will result in the accumulation of amino acids in the urinary tract. Henthorn et al. (2000) identified a variant in the SLC3A1 gene in cystinuric Newfoundland dogs. The mutation consists of a substitution of C for T in exon 2 (c.586C>T), and this change produces a stop codon that results in a truncated protein. No such mutation has been detected in other breeds of dogs with cystinuria. In addition to the described variant, other studies have reported different causative mutations in the SLC3A1 gene found in the English Bulldog (I192V and S698G) and Labrador (c.350delG). Currently, these three variants are not covered by our test.

Most affected breeds

English Bulldog
French Bulldog
Labrador
Landseer
Newfoundland

Bibliography

Brons AK, Henthorn PS, Raj K,et al. SLC3A1 and SLC7A9 mutations in autosomal recessive or dominant canine cystinuria: a new classification system. J Vet Intern Med. 2013 Nov-Dec;27(6):1400-8.

Harnevik L, Hoppe A, Söderkvist P. SLC7A9 cDNA cloning and mutational analysis of SLC3A1 and SLC7A9 in canine cystinuria. Mamm Genome. 2006 Jul;17(7):769-76.

Henthorn PS, Liu J, Gidalevich T,et al. Canine cystinuria: polymorphism in the canine SLC3A1 gene and identification of a nonsense mutation in cystinuric Newfoundland dogs. Hum Genet. 2000 Oct;107(4):295-303.