An APRT mutation is strongly associated with and likely causative for 2,8-dihydroxyadenine urolithiasis in dogs

Eva Furrow; Randall J Pfeifer; Carl A Osborne; Jody P Lulich

doi:10.1016/j.ymgme.2013.12.002

An APRT mutation is strongly associated with and likely causative for 2,8-dihydroxyadenine urolithiasis in dogs

Mol Genet Metab. 2014 Mar;111(3):399-403. doi: 10.1016/j.ymgme.2013.12.002. Epub 2013 Dec 11.

Authors

Eva Furrow¹, Randall J Pfeifer², Carl A Osborne³, Jody P Lulich⁴

Affiliations

¹ Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN 55108, USA. Electronic address: furro004@umn.edu.
² Department of Animal and Food Science, University of Wisconsin, River Falls, WI 54022, USA. Electronic address: randall.pfeifer@my.uwrf.edu.
³ Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN 55108, USA. Electronic address: osbor002@umn.edu.
⁴ Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN 55108, USA. Electronic address: lulic001@umn.edu.

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.

Keywords: 2,8-Dihydroxyadenine; Adenine phosphoribosyltransferase; Animal model; Genetics; Urolithiasis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenine / analogs & derivatives
Adenine Phosphoribosyltransferase / deficiency*
Adenine Phosphoribosyltransferase / genetics*
Animals
Dogs
High-Throughput Nucleotide Sequencing
Homozygote
Humans
Metabolism, Inborn Errors / genetics*
Metabolism, Inborn Errors / pathology
Metabolism, Inborn Errors / veterinary
Mutation, Missense*
Urolithiasis / genetics*
Urolithiasis / pathology
Urolithiasis / veterinary

Substances

2,8-dihydroxyadenine
Adenine Phosphoribosyltransferase
Adenine

Supplementary concepts

Adenine phosphoribosyltransferase deficiency

Grants and funding

T32 OD010993/OD/NIH HHS/United States