Mutations in the SLC2A9 Gene Cause Hyperuricosuria and Hyperuricemia in the Dog

Abstract

Allantoin is the end product of purine catabolism in all mammals except humans, great apes, and one breed of dog, the Dalmatian. Humans and Dalmatian dogs produce uric acid during purine degradation, which leads to elevated levels of uric acid in blood and urine and can result in significant diseases in both species. The defect in Dalmatians results from inefficient transport of uric acid in both the liver and renal proximal tubules. Hyperuricosuria and hyperuricemia (huu) is a simple autosomal recessive trait for which all Dalmatian dogs are homozygous. Therefore, in order to map the locus, an interbreed backcross was used. Linkage mapping localized the huu trait to CFA03, which excluded the obvious urate transporter 1 gene, SLC22A12. Positional cloning placed the locus in a minimal interval of 2.5 Mb with a LOD score of 17.45. A critical interval of 333 kb containing only four genes was homozygous in all Dalmatians. Sequence and expression analyses of the SLC2A9 gene indicated three possible mutations, a missense mutation (G616T;C188F) and two promoter mutations that together appear to reduce the expression levels of one of the isoforms. The missense mutation is associated with hyperuricosuria in the Dalmatian, while the promoter SNPs occur in other unaffected breeds of dog. Verification of the causative nature of these changes was obtained when hyperuricosuric dogs from several other breeds were found to possess the same combination of mutations as found in the Dalmatian. The Dalmatian dog model of hyperuricosuria and hyperuricemia underscores the importance of SLC2A9 for uric acid transport in mammals.

Author Summary

Animals excrete waste products in their urine. When most mammals metabolize compounds, called purines, they produce allantoin as one waste product in their urine. Humans, great apes, and Dalmatian dogs produce a different breakdown product, uric acid. This leads to high levels of uric acid in the urine and blood. In humans, this can result in diseases such as kidney stones and gout and may cause hypertension. In Dalmatians, high uric acid levels result in bladder stones that often have to be removed surgically. The cause of high uric acid levels in humans and great apes is not the same as in the Dalmatian dog. Here we report the genetic cause of the Dalmatian condition. This change is shared by dogs from unrelated breeds, indicating that it predates the separation of dog breeds. The gene that causes excretion of uric acid in Dalmatians is important for controlling the amount of uric acid in human blood and is therefore important for human diseases. It is not clear why humans and great apes have evolved to excrete uric acid, but it appears that some dogs have developed a different mechanism that leads to the same result: elevations in urine and blood uric acid levels.