Three diverse mutations underlying canine xanthine urolithiasis

Hereditary xanthinuria in people is an autosomal recessive disease caused by mutations in xanthine dehydrogenase (XDH) or molybdenum cofactor sulfurase (MOCOS). There are rare reports of hereditary xanthinuria in dogs, but genetic investigations have not previously been described. The purpose of this study was to uncover mutations underlying risk for canine xanthine urolithiasis by sequencing XDH and MOCOS in genomic DNA from affected dogs. The affected dogs included two Toy Manchester Terriers (TMT), two Cavalier King Charles Spaniels (CKCS), and a mixed breed dog. Three putative causal mutations were found. The TMT dogs had a homozygous splice site mutation in MOCOS, the CKCS dogs had a homozygous nonsense mutation in MOCOS, and the mixed breed dog had a homozygous splice site mutation in XDH, cDNA sequencing verified aberrant splicing for the two splice site mutations. Mutation assays were developed to determine the allele frequencies of the mutations in populations of TMT and CKCS dogs without a history of xanthine urolithiasis. Of 49 TMT dogs tested. 37 were clear, 10 were earners, and 2 were homozygous for the TMT mutation. Urine was analyzed from the 2 homozygous TMTs and revealed xanthinuria. Of 108 CKCS dogs tested. 105 were clear, 3 were earners, and none were homozygous for the CKCS mutation. In conclusion, diverse mutations were found to be responsible for hereditary xanthinuria in dogs, and we have developed genetic tests for these forms of the disease. Genetic testing can help inform breeders and identify dogs that may benefit from preventative therapies.