title: 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.
authors.affiliation: Department of Population Health and Reproduction, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America. dlbannasch@ucdavis.edu
authors.forename: Danika
authors.initials: D
authors.lastname: Bannasch
authors.forename: Noa
authors.initials: N
authors.lastname: Safra
authors.forename: Amy
authors.initials: A
authors.lastname: Young
authors.forename: Nili
authors.initials: N
authors.lastname: Karmi
authors.forename: R S
authors.initials: RS
authors.lastname: Schaible
authors.forename: G V
authors.initials: GV
authors.lastname: Ling
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002874:Chromosome Mapping; D004283:Dog Diseases / Q000235:genetics* / Q000652:urine; D004285:Dogs; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics* / Q000378:metabolism; D033461:Hyperuricemia / Q000235:genetics* / Q000652:urine / Q000662:veterinary*; D008969:Molecular Sequence Data; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D014527:Uric Acid / Q000097:blood / Q000652:urine*
chemical_list: D051246:Glucose Transport Proteins, Facilitative; D020033:Protein Isoforms; D014527:Uric Acid