Cystinuria Type II-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 dominant mode of inheritance. Autosomal dominant inheritance means that dogs only have to inherit one copy of the mutation or pathogenic variant to be at risk of developing the disease. Each puppy born to a parent carrying one copy of the mutation has a 50% chance of inheriting one copy of the mutation and being at risk for the disease. Breeding between dogs carrying genetic variants that can cause disease is not recommended, even if they do not show symptoms.

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 cause the accumulation of amino acids in the urinary tract. A variant in the SLC3A1 gene responsible for type II-A cystinuria has been identified in the Australian Cattle Dog. The mutation results in a 6 base pair deletion in exon 6, which causes the deletion of 2 of 3 adjacent threonine residues in the translated protein. This alteration of the protein sequence affects a highly conserved portion of the extracellular domain involved in the transport of substances. This suggests that the described variant may interfere with the transport function of the protein.

Most affected breeds

Australian Cattle Dog

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.