Mutations in the SLC3A1 Gene in Cystinuric Patients: Frequencies and Identification of a Novel Mutation

Abstract

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.

Identification of 12 novel mutations in the SLC3A1 gene in Swedish cystinuria patients

“…Previous work leads us to postulate that SLC3A1 mutations are responsible only for type I cystinuria, still mutations in the SLC3A1 gene are not detected in all cystinuria type I patients Horsford et al, 1996;Goodyer et al, 1998;Saadi et al, 1998;Albers et al, 1999]. The patients in the present study were not biochemically classified as type I-or non-type I cystinuria and therefore the absence of mutations in SLC3A1 in some individuals may be explained by mutations in a non-type I cystinuria locus, most likely the recently cloned SLC7A9 gene.…”

“…To date more than 40 different mutations have been reported in the SLC3A1 gene in cystinuria patients from populations in Italy and Spain [Calonge et al, 1994;Gasparini et al, 1995;Bisceglia et al, 1996;Albers et al, 1999], the Middle East [Pras et al, 1995], Japan [Miyamoto et al, 1995;Egoshi et al, 2000], Canada [Horsford et al, 1996;Saadi et al, 1998], and the United States [Gitomer et al, 1998]. The mutations tend to be population-specific although there are a few that occur worldwide.…”

Genotype and Phenotype Analysis in Pediatric Patients with Cystinuria

“…This mutation is common in South-eastern European (1718), Gypsy (19), and Greek populations (20) but has not been found in Chinese (21) and Japanese (22) patients. Conversely, the SLC7A9 p.P482L mutation is common in Japanese patients (22), but has not been found in European populations.…”

Cystinuria-specific rBAT(R365W) mutation reveals two translocation pathways in the amino acid transporter rBAT-b0,+AT

“…In the present study, we functionally characterized the R365W mutation of human rBAT, which was found in three cystinuria patients [29]; additionally, a mutation to leucine at the same position (R365L) was reported in another patient [34]. Interestingly, the rBAT mutation R365W combines a trafficking defect with altered functional properties of the transporter b 0,+ .…”