SLC3A1andSLC7A9Mutations in Autosomal Recessive or Dominant Canine Cystinuria: A New Classification System

Abstract

Background Cystinuria, one of the first recognized inborn errors of metabolism, has been reported in many dog breeds. Hypothesis/Objectives To determine urinary cystine concentrations, inheritance and mutations in the SLC3A1 and SLC7A9 genes associated with cystinuria in 3 breeds. Animals Mixed and purebred Labrador Retrievers (n=6), Australian Cattle Dogs (6), Miniature Pinschers (4) and 1 mixed breed dog with cystine urolithiasis, relatives and control dogs. Methods Urinary cystinuria and aminoaciduria was assessed and exons of the SLC3A1 and SLC7A9 genes were sequenced from genomic DNA. Results In each breed, male and female dogs, independent of neuter status, were found to form calculi. A frameshift mutation in SLC3A1 (c.350delG) resulting in a premature stop codon was identified in autosomal-recessive (AR) cystinuria in Labrador Retrievers and mixed breed dogs. A 6 bp deletion (c.1095_1100del) removing 2 threonines in SLC3A1 was found in autosomal-dominant (AD) cystinuria with a more severe phenotype in homozygous than in heterozygous Australian Cattle Dogs. A missense mutation in SLC7A9 (c.964G>A) was discovered in AD cystinuria in Miniature Pinschers with only heterozygous affected dogs observed to date. Breed specific DNA tests were developed, but the prevalence of each mutation remains unknown. Conclusions and clinical importance These studies describe the first AD inheritance and the first putative SLC7A9 mutation to cause cystinuria in dogs and expand our understanding of this phenotypically and genetically heterogeneous disease, leading to a new classification system for canine cystinuria and better therapeutic management and genetic control in these breeds.

Characteristics of urolithiasis in the dog population of Hungary from 2001 to 2012

“…the Newfoundland dog and the Labrador Retriever (Henthorn et al, 2000;Bannasch and Henthorn, 2009), were not represented in our series except for a single sample submitted from a Labrador Retriever. Our results suggest, accord-ing to the recently published classification system (Brons et al, 2013), that Type III androgen-dependent cystinuria may be the most common form in our dog population as only male individuals were affected.…”

“…Irish Terriers are known to be highly predisposed to cystinuria (Brons et al, 2013). In the present study, all three samples from Irish Terriers were pure cystine stones.…”

Etiopatogenia Da Urolitíase Em Cães

“…A suscetibilidade genética a determinados tipos de urólitos, pode ser compartilhada por cães e humanos (FURROW et al, 2013), como por exemplo na cistinúria causada por mutação do gene SCL3A1 (BRONS et al, 2013) e na excreção de 2,8-diidroxiadenina causada por mutação no gene APRT (FURROW et al, 2013).…”

“…Isso deve-se à identificação facilitada das alterações fisiológicas envolvidas e principalmente dos padrões de herança nas urolitíases mais raras (DANPURE, 2000). Raças caninas, por possuírem diversidade genética relativamente baixa, representam uma oportunidade de estudo dos determinantes genéticos das diferentes enfermidades (BRONS et al, 2013). Quando uma raça possui predisposição a um tipo particular de urólitos, provavelmente há algum fator genético primordial envolvido (BANNASCH & HENTHORN, 2008).…”

“…Quando uma raça possui predisposição a um tipo particular de urólitos, provavelmente há algum fator genético primordial envolvido (BANNASCH & HENTHORN, 2008). Estudar os determinantes genéticos em raças caninas predispostas é uma maneira eficiente de compreender o problema em humanos, pois algumas alterações genéticas são semelhantes nas duas espécies (BRONS et al, 2013).…”