This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cystinuria is an inherited renal disease characterized by defective amino acid reabsorption and by the formation of cystine uroliths. Different forms of the disease, designated type I and non-type I, can be distinguished clinically and biochemically, and have been associated in cystinuric humans with mutations in the SLC3A1 (rBAT) and SLC7A9 genes, respectively. Cystinuria is primarily inherited as an autosomal recessive trait in humans and the type I form of the disease is most common. Cystinuria has been recognized in many breeds of dogs and a severe form, resembling type I cystinuria, has been characterized in the Newfoundland breed. Breeding studies (supported by this grant) previously demonstrated autosomal recessive inheritance of cystinuria in the Newfoundland dog, suggesting SLC3A1 as a candidate gene for the disease. We cloned and sequenced the canine SLC3A1 cDNA and gene from normal and affected Newfoundland dogs and identified a nonsense mutation in exon 2 of the gene in the cystinuric dogs. This discovery confirms the Newfoundland disease as a true homologue of human type I cystinuria. The knowledge of the gene mutation in the canine model provides the opportunity to use a large animal model to investigate molecular approaches for the treatment of cystinuria and other renal tubular diseases. Studies are also ongoing to investigate cystinuria in the Maned Wolf, a threatened South American canid species with an extremely high incidence of cystinuria. We have analyzed urine samples from many captive animals in the United States in order to determine the mode of inheritance and characterize the type of cystinuria. These studies are ongoing and funded in part by the Morris Animal Foundation.
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