Genetic disorders – Development
Molecular genetics of cystinuria: Mutation analysis of SLC3A1 and evidence for another gene in the Type I (silent) phenotype

https://doi.org/10.1046/j.1523-1755.1998.00956.xGet rights and content
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Molecular genetics of cystinuria: Mutation analysis of SLC3A1 and evidence for another gene in the Type I (silent) phenotype.

Background

Cystinuria is a hereditary disorder that affects luminal transport of cystine and dibasic amino acids in kidney and small intestine. Three subtypes have been defined on the basis of urinary excretion of cystine in obligate heterozygotes. Mutations in the SLC3A1 gene have been associated with the Type I phenotype.

Methods

We investigated 20 cystinuria patients from Quebec (8 Type I/I, 9 Type I/III and 3 Type II/N) for mutations in SLC3A1. DNA was studied by Southern blotting and by the single strand conformation polymorphism (SSCP) protocol to identify mutations. Expression of mutations in Xenopus oocytes was performed to confirm the effect of missense mutations on cystine uptake.

Results

Six novel mutations (2 large deletions, a 2 bp deletion and 3 single bp substitutions) were identified on the Type I allele. Four missense mutations (T216M, S217R, R270L and I618M) were expressed in vitro; the first three changes significantly decreased uptake.

Conclusions

Combined with our previous work, we have identified 15/16 mutations in SLC3A1 on Type I alleles in the eight Type I/I patients, but only one SLC3A1 mutation on the nine Type I alleles of the Type I/III patients. Therefore, we propose that the Type I phenotype could be caused by mutations in other, as yet unidentified cystinuria genes.

Keywords

amino acids
transport
inherited disorders
obligate heterozygotes
allelic variation
gene mapping

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See Editorial by Chesney, p. 279