Mutations in the SLC3A1 gene in cystinuric patients: frequencies and identification of a novel mutation.

Cystinuria is a frequent autosomal recessive transport disorder characterized by defective renal resorption of cystine and other dibasic amino acids. Biochemically, three types of cystinuria can be defined. Here we present our results of screening for mutations in the SLC3A1 gene, which codes for a dibasic amino acid transporter protein and appears to be involved in the pathogenesis of cystinuria type I. Our study population consists of 5 Italian cystinuria type I patients and 10 cystinuric patients as yet unclassified as to clinical type. The latter were of different ethnic origin. In total, we found 13 point mutations and 8 genomic rearrangements in 15 cystinuric patients, i.e., our detection rate was 70% (23/30 chromosomes). Remarkably, in patients known to be suffering from cystinuria type I, the mutation detection rate was only 50%, whereas in patients unselected as to cystinuria type, we found 80% of mutations. Additionally, our results, as with those published in the literature, indicate a possible population specific distribution of mutations: Each of the 4 Greek patients analyzed here showed homozygosity for mutation T216M in exon 3. Analysis of a Yugoslavian patient showed homozygosity for a novel mutation, R365L, in exon 6 (nt1094G > T). Findings from molecular genetic studies, as well as physiological investigations, suggest that there are further genes that play a role in the etiology of cystinuria. Nevertheless, our results show that screening for mutations in the SLC3A1 gene can be a meaningful step toward molecular genetic diagnosis of cystinuria in patients without biochemical classification. As with cystic fibrosis, the finding of specific mutations in particular ethnic populations, suggest that the diagnostic approach should take into consideration a patient's ethnic origins.