Functional analysis of mutations in SLC7A9, and genotype-phenotype correlation in non-type I cystinuria

Mariona Font, Lídia Feliubadaló, Xavier P. 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, Marta Manzoni, Mirko Riboni, Andrea Ballabio, Giuseppe Borsani, Núria Reig, Esperanza Fernández, Antonio Zorzano & 2 others Joan Bertran, Manuel Palacín

Research output: Contribution to journalArticle

100 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)305-316
Number of pages12
JournalHuman Molecular Genetics
Volume10
Issue number4
Publication statusPublished - 15 Feb 2001
Externally publishedYes

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Cystinuria
Genetic Association Studies
Mutation
Heterozygote
Cystine
Diamino Amino Acids
Phenotype
Genetic Databases
Nephrolithiasis
Missense Mutation
HeLa Cells
Genes
Exons
Alleles

ASJC Scopus subject areas

  • Genetics

Cite this

Font, M., Feliubadaló, L., Estivill, X. P., Nunes, V., Golomb, E., Kreiss, Y., ... Palacín, M. (2001). Functional analysis of mutations in SLC7A9, and genotype-phenotype correlation in non-type I cystinuria. Human Molecular Genetics, 10(4), 305-316.

Functional analysis of mutations in SLC7A9, and genotype-phenotype correlation in non-type I cystinuria. / Font, Mariona; Feliubadaló, Lídia; Estivill, Xavier P.; Nunes, Virginia; Golomb, Eliahu; Kreiss, Yitshak; Pras, Elon; Bisceglia, Luigi; D'Adamo, Adamo P.; Zelante, Leopoldo; Gasparini, Paolo; Bassi, Maria Teresa; George, Alfred L.; Manzoni, Marta; Riboni, Mirko; Ballabio, Andrea; Borsani, Giuseppe; Reig, Núria; Fernández, Esperanza; Zorzano, Antonio; Bertran, Joan; Palacín, Manuel.

In: Human Molecular Genetics, Vol. 10, No. 4, 15.02.2001, p. 305-316.

Research output: Contribution to journalArticle

Font, M, Feliubadaló, L, Estivill, XP, Nunes, V, Golomb, E, Kreiss, Y, Pras, E, Bisceglia, L, D'Adamo, AP, Zelante, L, Gasparini, P, Bassi, MT, George, AL, Manzoni, M, Riboni, M, Ballabio, A, Borsani, G, Reig, N, Fernández, E, Zorzano, A, Bertran, J & Palacín, M 2001, 'Functional analysis of mutations in SLC7A9, and genotype-phenotype correlation in non-type I cystinuria', Human Molecular Genetics, vol. 10, no. 4, pp. 305-316.
Font, Mariona ; Feliubadaló, Lídia ; Estivill, Xavier P. ; Nunes, Virginia ; Golomb, Eliahu ; Kreiss, Yitshak ; Pras, Elon ; Bisceglia, Luigi ; D'Adamo, Adamo P. ; Zelante, Leopoldo ; Gasparini, Paolo ; Bassi, Maria Teresa ; George, Alfred L. ; Manzoni, Marta ; Riboni, Mirko ; Ballabio, Andrea ; Borsani, Giuseppe ; Reig, Núria ; Fernández, Esperanza ; Zorzano, Antonio ; Bertran, Joan ; Palacín, Manuel. / Functional analysis of mutations in SLC7A9, and genotype-phenotype correlation in non-type I cystinuria. In: Human Molecular Genetics. 2001 ; Vol. 10, No. 4. pp. 305-316.
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abstract = "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.",
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AU - Font, Mariona

AU - Feliubadaló, Lídia

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AU - Nunes, Virginia

AU - Golomb, Eliahu

AU - Kreiss, Yitshak

AU - Pras, Elon

AU - Bisceglia, Luigi

AU - D'Adamo, Adamo P.

AU - Zelante, Leopoldo

AU - Gasparini, Paolo

AU - Bassi, Maria Teresa

AU - George, Alfred L.

AU - Manzoni, Marta

AU - Riboni, Mirko

AU - Ballabio, Andrea

AU - Borsani, Giuseppe

AU - Reig, Núria

AU - Fernández, Esperanza

AU - Zorzano, Antonio

AU - Bertran, Joan

AU - Palacín, Manuel

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N2 - 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.

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