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Human Molecular Genetics, 2001, Vol. 10, No. 4 305-316
© 2001 Oxford University Press

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

Mariona Font1,+, Lídia Feliubadaló1,2, Xavier Estivill1, Virginia Nunes1, Eliahu Golomb3, Yitshak Kreiss4, Elon Pras4,5, Luigi Bisceglia6,+, Adamo P. d’Adamo6, Leopoldo Zelante6, Paolo Gasparini6, Maria Teresa Bassi7,+, Alfred L. George Jr8,9, Marta Manzoni7, Mirko Riboni7, Andrea Ballabio7, Giuseppe Borsani7, Núria Reig2,+, Esperanza Fernández2, Antonio Zorzano2, Joan Bertran2 and Manuel Palacín2,§

1Centre de Genètica Mèdica i Molecular (IRO), Hospital Duran i Reynals, Autovía de Castelldefels Km 2.7, L’Hospitalet de Llobregat, E-08907 Barcelona, Spain, 2Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Avenida Diagonal 645, E-08028 Barcelona, Spain, 3Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel, 4Department of Medicine C, 5Institute of Human Genetics, Tel Hashomer 52621, Israel (affiliated to the Sackler School of Medicine) Tel Aviv University, Tel Aviv 69978, Israel, 6Medical Genetics Service, IRCCS-Hospital ‘CSS’, San Giovanni Rotondo, Italy, 7Telethon Institute of Genetics and Medicine (TIGEM), Via Pietro Castellino 111, I-80131 Napoli, Italy and Divisions of 8Genetic Medicine and 9Nephrology, Vanderbilt University Department of Medicine, Nashville, TN 37232, USA

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.

+ These authors contributed equally to this work

§ To whom correspondence should be addressed. Tel: +34 93 4034617; Fax: +34 93 4021559; Email: mpalacin@porthos.bio.ub.es


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