A mutation in the canine multidrug resistance gene, MDR1, has previously been associated with drug sensitivities in two breeds from the collie lineage. We exploited breed phylogeny and reports of drug sensitivity to survey other purebred populations that might be genetically at risk. We found that the same allele, mdr1-1⌬, segregated in seven additional breeds, including two sighthounds that were not expected to share collie ancestry. A mutant haplotype that was conserved among affected breeds indicated that the allele was identical by descent. Based on breed histories and the extent of linkage disequilibrium, we conclude that all dogs carrying mdr1-1⌬ are descendants of a dog that lived in Great Britain before the genetic isolation of breeds by registry (ca. 1873). The breed distribution and frequency of mdr1-1⌬ have applications in veterinary medicine and selective breeding, whereas the allele's history recounts the emergence of formally recognized breeds from an admixed population of working sheepdogs.allele age ͉ Canis familiaris ͉ drug sensitivity ͉ identity by descent ͉ P-glycoprotein T he introduction of a new parasiticide in the 1980s (1) uncovered a preexisting mutation in dogs that predisposes animals to a potentially fatal neurotoxicosis (2, 3). The drug, ivermectin, exerts antiparasitic action by potentiating ligandgated chloride ion channels in the peripheral nervous system of several invertebrate phyla (4-7). The resulting influx of chloride ions silences synaptic transmissions, thereby causing lethal paralysis in nematode and arthropod parasites. Ivermectin is generally safe for use in domestic animals because the homologous mammalian targets are restricted to the CNS (8, 9) where they are shielded by the blood-brain barrier (reviewed in ref. 10). A principal component of this protective barrier is Pglycoprotein, an ATP-dependent drug transporter that moves a broad spectrum of substrates across several important tissue borders (11). P-glycoprotein is encoded by the multiple drug resistance gene, MDR1.The earliest indication that ivermectin neurotoxicity was caused by a defect in the blood-brain barrier came from an observation that affected dogs had elevated concentrations of ivermectin in the CNS (12). Almost a decade later, a similar phenotype was observed in knockout mice lacking Abcb1a, the murine ortholog of MDR1 (13). Mealey et al. (14) investigated canine MDR1 as a candidate gene for ivermectin sensitivity and discovered that affected Collies were homozygous for a 4-bp deletion in the fourth exon. The mutation, mdr1-1⌬, causes a frameshift accompanied by multiple premature stop codons, presumably resulting in a severely truncated P-glycoprotein composed of Ͻ10% of the wild-type amino acid sequence. This allele probably results in a complete loss of Pglycoprotein function, although this fact has not yet been formally established (15). More than 20 therapeutic drugs are known substrates of P-glycoprotein. Recently, three of these drugs were found to interact with mdr1-1⌬ and cause toxic reac...

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.