Journal Article

Functional analysis of mutations in <i>SLC7A9</i>, and genotype–phenotype correlation in non-Type I cystinuria

Mariona Font, Lídia Feliubadaló, Xavier Estivill, Virginia Nunes, Eliahu Golomb, Yitshak Kreiss, Elon Pras, Luigi Bisceglia, Adamo P. d’Adamo, Leopoldo Zelante, Paolo Gasparini, Maria Teresa Bassi, Alfred L. George Jr, Marta Manzoni, Mirko Riboni, Andrea Ballabio, Giuseppe Borsani, Núria Reig, Esperanza Fernández, Antonio Zorzano, Joan Bertran and Manuel Palacín

in Human Molecular Genetics

Volume 10, issue 4, pages 305-316
Published in print February 2001 | ISSN: 0964-6906
Published online February 2001 | e-ISSN: 1460-2083 | DOI:
Functional analysis of mutations in SLC7A9, and genotype–phenotype correlation in non-Type I cystinuria

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Cystinuria (OMIM 220100) is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids that results in nephrolithiasis of cystine. Mutations in SLC3A1, which encodes rBAT, cause Type I cystinuria, and mutations in SLC7A9, which encodes a putative subunit of rBAT (bo,+AT), cause non-Type I cystinuria. Here we describe the genomic structure of SLC7A9 (13 exons) and 28 new mutations in this gene that, together with the seven previously reported, explain 79% of the alleles in 61 non-Type I cystinuria patients. These data demonstrate that SLC7A9 is the main non-Type I cystinuria gene. Mutations G105R, V170M, A182T and R333W are the most frequent SLC7A9 missense mutations found. Among heterozygotes carrying these mutations, A182T heterozygotes showed the lowest urinary excretion values of cystine and dibasic amino acids. Functional analysis of mutation A182T after co-expression with rBAT in HeLa cells revealed significant residual transport activity. In contrast, mutations G105R, V170M and R333W are associated to a complete or almost complete loss of transport activity, leading to a more severe urinary phenotype in heterozygotes. SLC7A9 mutations located in the putative transmembrane domains of bo,+AT and affecting conserved amino acid residues with a small side chain generate a severe phenotype, while mutations in non-conserved residues give rise to a mild phenotype. These data provide the first genotype–phenotype correlation in non-Type I cystinuria, and show that a mild urinary phenotype in heterozygotes may associate with mutations with significant residual transport activity.

Journal Article.  9078 words.  Illustrated.

Subjects: Genetics and Genomics

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