RESUMO
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.
Assuntos
Sistemas de Transporte de Aminoácidos Básicos , Proteínas de Transporte/genética , Cistinúria/genética , Mutação da Fase de Leitura , Glicoproteínas de Membrana/genética , Mutação de Sentido Incorreto , Sequência de Aminoácidos , Animais , Células COS , Cromossomos Humanos Par 19 , Cistinúria/etnologia , DNA Complementar/análise , Feminino , Humanos , Itália , Judeus , Líbia , Masculino , Modelos Biológicos , Dados de Sequência Molecular , América do Norte , Linhagem , Homologia de Sequência de Aminoácidos , Espanha , Distribuição TecidualAssuntos
Colágeno/genética , Nefrite Hereditária/genética , Cromossomo X/genética , Adolescente , Adulto , Sequência de Aminoácidos , Substituição de Aminoácidos , Criança , DNA/química , DNA/genética , Análise Mutacional de DNA , Feminino , Ligação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Nefrite Hereditária/patologia , Mutação Puntual , Polimorfismo Conformacional de Fita Simples , Homologia de Sequência de AminoácidosRESUMO
Urinary excretion of the most widely studied renal stone promoting (calcium, oxalate, uric acid and phosphate) and inhibiting (citrate, magnesium, pyrophosphate and glycosaminoglycans) factors, as well as the Tamm-Horsfall mucoprotein, was evaluated in 14 children with idiopathic calcium nephrolithiasis, 6 children with renal stone disease secondary to excretory malformations and 19 normal controls. No statistically significant differences in urinary excretion of promoting and inhibiting factors were found in children with idiopathic calcium nephrolithiasis but the relationship between promoting and inhibiting factors was changed as shown by an abnormal ratio of oxalate/citrate X glycosaminoglycans. This finding suggests that there is an imbalance between promoting and inhibiting factors in children with idiopathic calcium nephrolithiasis, and it is not detected by assay of each single substance.
