SLC3A1 and SLC7A9 mutations in autosomal recessive or dominant canine cystinuria: a new classification system.

Cystinuria (OMIA 000256-9615) is one of the first inborn errors of metabolism recognized by Sir Archibald Garrod 1,2 and is an inherited selective renal transport defect 3,4 involving cystine and the dibasic amino acids ornithine, lysine and arginine, collectively known as COLA.4 In contrast to the normal near complete reabsorption of COLA in the proximal renal tubules, these amino acids reach high concentrations in the urine in affected individuals, but only cystine causes a clinical problem.5 The low solubility of cystine in acidic and neutral urine may lead to the formation of cystine crystals and uroliths in the urinary tract,6 which result clinically in stranguria, hematuria, urinary obstruction and renal failure.7,8 In 1823, cystinuria was the first reported inborn error of metabolism in dogs,9 and now is known to affect >70 canine breeds according to reports of veterinary urolith analysis laboratories worldwide.10,11 Based upon the varied clinical presentations, metabolic derangements and genetic studies, we previously divided canine cystinuria into type I and non-type I cystinuria.12 Type I cystinuria has been characterized in Newfoundlands and Landseers,13 and causes massive aminoaciduria of COLA and juvenile to adult onset calculi formation. It is an autosomal recessive trait affecting both males and females independent of neutering status, although more often cystinuric males show clinical signs of urinary obstruction, presumably due to anatomical differences between males and females.13 In non-type I cystinuria, exemplified by Mastiffs and related breeds, Scottish Deerhounds, and Irish Terriers, only intact adult males show variable degrees of aminoaciduria and the average age of urolith formation is later than in Newfoundlands. The molecular basis and mode of inheritance of non-type I cystinuria remain unknown, but it is not an X-chromosomal disorder and appears to be testosterone dependent. a,14 Two genes, SLC3A1 and SLC7A9, encode the subunits of b0,+, the basic amino acid transporter system. 4,15,16 The SLC3A1 gene encodes the extracellular heavy chain referred to as rBAT, and the SLC7A9 gene the light chain called b0,+AT.3 The subunit b0,+AT has 12 transmembrane domains typical of cell membrane transporters and heterodimerizes with rBAT exclusively to form the COLA amino acid transporter.17 Among all the cystinuric dogs to date, only 1 mutation in SLC3A1, an early stop codon precluding the production of the rBAT protein, and leading to the loss of b0,+ function, was identified in cystinuric Newfoundlands in 2000.18 And although the disease was widely recognized in the breed, screening programs for the mutation have markedly decreased the incidence of cystinuria in Newfoundlands and Landseers worldwide. We report here the clinical, metabolic and molecular genetic characterization of cystinuric Labrador Retrievers, Australian Cattle Dogs, Miniature Pinschers and mixed breed dogs. Because our data demonstrate multiple genetic etiologies and modes of inheritance for cystinuria, we propose a new expanded classification system for canine cystinuria.