Canine cystinuria: polymorphism in the canine SLC3A1 gene and identification of a nonsense mutation in cystinuric Newfoundland dogs

Cystinuria is an inherited renal and intestinal disease characterized by de fective amino acid reabsorption and cystine urolithiasis. Different forms o f the disease, designated type I and non-type I in cystinuric humans, can b e distinguished clinically and biochemically, and have been associated with mutations in the SLC3A1 (rBAT) and SLC7A9 genes, respectively. Type I cyst inuria is the most common form and is inherited as an autosomal recessive t rait in humans. Cystinuria has been recognized in more than 60 breeds of do gs and a severe form, resembling type I cystinuria, has been characterized in the Newfoundland breed. Here we report the cloning and sequencing of the canine SLC3A1 cDNA and gene, and the identification of a nonsense mutation in exon 2 of the gene in cystinuric Newfoundland dogs. A mutation-specific test was developed for the diagnosis and control of cystinuria in Newfound land dogs. In cystinuric dogs of six other breeds, either heterozygosity at the SLC3A1 locus or lack of mutations in the coding region of the SLC3A1 g ene were observed, indicating that cystinuria is genetically heterogeneous in dogs, as it is in humans. The canine homologue of human type I cystinuri a provides the opportunity to use a large animal model to investigate molec ular approaches for the treatment of cystinuria and other renal tubular dis eases.