Cystinuria is an autosomal recessive disorder of the kidneys and intestine with defective luminal transport of cystine and other dibasic amino acids (ornithine, arginine, and lysine). Three phenotypes have been described, based on urinary excretion of these amino acids in obligate heterozygotes: Type I (silent carriers); Type II (moderate elevation); and Type III (mild elevation). The SLC3AI (D2H) protein has been shown to enhance cystine reabsorption and mutations in D2H have been reported in cystinuria. The aims of this study were to characterize D2H gene structure and to identify mutations in Quebec patients. / The D2H cDNA was used to isolate five genomic clones and to characterize the entire gene. The gene spans over 40 kb and contains 10 exons. SSCP and Southern blotting techniques were successful in identifying six novel mutations (2 large deletions, 3 missense mutations, and one 2bp deletion) in twenty cystinuric patients (8 Type I/I, 9 Type I/III, and 3 Type II/N). / Our group has identified mutations in the SLC3A1 gene on 15 of 25 cystinuria chromosomes. All but one of these mutations have been found on patients with Type I/I phenotype (the remaining mutation was identified on a Type I/III patient). These studies have revealed eight mutations unique to Quebec and indicate population-specificity and genetic heterogeneity. Furthermore, SLC3A1 mutations only account for Type I cystinuria. However, since only 1 SLC3A1 mutation was identified in 9 Type I/III patients, the data suggest that another gene(s) is (are) responsible for the Type I/N phenotype in some patients.

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