title: An APRT mutation is strongly associated with and likely causative for 2,8-dihydroxyadenine urolithiasis in dogs.
abstract: 2,8-Dihydroxyadenine (2,8-DHA) urolithiasis in people is caused by autosomal recessive mutations in the adenine phosphoribosyltransferase gene (APRT). 2,8-DHA urolithiasis has recently been reported in two dogs, but, to the authors' knowledge, no studies have yet investigated the genetic basis for susceptibility to the development of 2,8-DHA urolithiasis in this species. Our aim was to sequence APRT in dogs affected by 2,8-DHA urolithiasis and compare the results to clinically healthy dogs of similar ancestral lineages. Our hypothesis was that we would identify an autosomal recessive mutation in APRT that is associated with the disease. The case population consisted of six dogs with a history of 2,8-DHA urolithiasis: five Native American Indian Dogs (NAIDs) and a mixed breed. The control population consisted of adult NAIDs with no history of urolithiasis. We sequenced APRT and identified a missense mutation in a highly conserved codon of APRT (c.260G>A; p.Arg87Gln). The c.260A mutation was present in a homozygous state in all six dogs with 2,8-DHA urolithiasis, and it was strongly associated with the disease. This exact missense mutation has been previously reported to cause loss of APRT enzyme function in a human cell line, and it is likely a causative mutation in dogs. Therefore, the dog offers a naturally-occurring genetic animal model for 2,8-DHA urolithiasis.
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN 55108, USA. Electronic address: furro004@umn.edu.
authors.forename: Eva
authors.initials: E
authors.lastname: Furrow
authors.affiliation: Department of Animal and Food Science, University of Wisconsin, River Falls, WI 54022, USA. Electronic address: randall.pfeifer@my.uwrf.edu.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Pfeifer
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN 55108, USA. Electronic address: osbor002@umn.edu.
authors.forename: Carl A
authors.initials: CA
authors.lastname: Osborne
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN 55108, USA. Electronic address: lulic001@umn.edu.
authors.forename: Jody P
authors.initials: JP
authors.lastname: Lulich
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000228:Adenine Phosphoribosyltransferase / Q000172:deficiency* / Q000235:genetics*; D000818:Animals; D004285:Dogs; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D008661:Metabolism, Inborn Errors / Q000235:genetics* / Q000473:pathology / Q000662:veterinary; D020125:Mutation, Missense; D052878:Urolithiasis / Q000235:genetics* / Q000473:pathology / Q000662:veterinary
chemical_list: C002993:2,8-dihydroxyadenine; D000228:Adenine Phosphoribosyltransferase; D000225:Adenine
keywords: 2,8-Dihydroxyadenine; Adenine phosphoribosyltransferase; Animal model; Genetics; Urolithiasis