title: Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (bo,+AT) of rBAT.
abstract: Cystinuria (MIM 220100) is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids. Mutations in SLC3A1, encoding rBAT, cause cystinuria type I (ref. 1), but not other types of cystinuria (ref. 2). A gene whose mutation causes non-type I cystinuria has been mapped by linkage analysis to 19q12-13.1 (Refs 3,4). We have identified a new transcript, encoding a protein (bo, +AT, for bo,+ amino acid transporter) belonging to a family of light subunits of amino acid transporters, expressed in kidney, liver, small intestine and placenta, and localized its gene (SLC7A9) to the non-type I cystinuria 19q locus. Co-transfection of bo,+AT and rBAT brings the latter to the plasma membrane, and results in the uptake of L-arginine in COS cells. We have found SLC7A9 mutations in Libyan-Jews, North American, Italian and Spanish non-type I cystinuria patients. The Libyan Jewish patients are homozygous for a founder missense mutation (V170M) that abolishes b o,+AT amino-acid uptake activity when co-transfected with rBAT in COS cells. We identified four missense mutations (G105R, A182T, G195R and G295R) and two frameshift (520insT and 596delTG) mutations in other patients. Our data establish that mutations in SLC7A9 cause non-type I cystinuria, and suggest that bo,+AT is the light subunit of rBAT.
authors.affiliation: Centre de Genètica Mèdica i Molecular (IRO), Hospital Duran i Reynals, Autovía de Castelldefels Km 2.7, L'Hospitalet de Llobregat, Barcelona, E-08907, Spain.
authors.forename: L
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authors.lastname: Feliubadaló
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authors.lastname: Font
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authors.lastname: Purroy
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authors.lastname: Rousaud
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authors.lastname: Golomb
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authors.lastname: Centola
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authors.lastname: Aksentijevich
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authors.lastname: Bisceglia
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authors.lastname: Gallucci
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authors.lastname: de Sanctis
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authors.lastname: Ponzone
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authors.lastname: Rizzoni
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authors.lastname: Zelante
authors.forename: M T
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authors.lastname: Bassi
authors.forename: A L
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authors.lastname: George
authors.forename: M
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authors.lastname: Manzoni
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authors.lastname: De Grandi
authors.forename: M
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authors.lastname: Riboni
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authors.initials: JK
authors.lastname: Endsley
authors.forename: A
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authors.lastname: Ballabio
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authors.lastname: Borsani
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authors.lastname: Reig
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authors.lastname: Fernández
authors.forename: R
authors.initials: R
authors.lastname: Estévez
authors.forename: M
authors.initials: M
authors.lastname: Pineda
authors.forename: D
authors.initials: D
authors.lastname: Torrents
authors.forename: M
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authors.lastname: Camps
authors.forename: J
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authors.lastname: Lloberas
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authors.lastname: Zorzano
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authors.lastname: Palacín
mesh_terms: D000595:Amino Acid Sequence; D026923:Amino Acid Transport Systems, Basic; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics*; D002888:Chromosomes, Human, Pair 19; D003555:Cystinuria / Q000208:ethnology / Q000235:genetics*; D018076:DNA, Complementary / Q000032:analysis; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D007558:Italy; D007585:Jews; D008002:Libya; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008954:Models, Biological; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009656:North America; D010375:Pedigree; D017386:Sequence Homology, Amino Acid; D013030:Spain; D014018:Tissue Distribution
chemical_list: D026923:Amino Acid Transport Systems, Basic; D002352:Carrier Proteins; D018076:DNA, Complementary; D008562:Membrane Glycoproteins; C499489:SLC7A9 protein, human