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

被引:101
作者
Font, M
Feliubadaló, L
Estivill, X
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
机构
[1] Univ Barcelona, Fac Biol, Dept Bioquim & Biol Mol, E-08028 Barcelona, Spain
[2] Hosp Duran I Reynals, IRO, Ctr Genet Med & Mol, E-08907 Barcelona, Spain
[3] Hosp CSS, IRCCS, Med Genet Serv, San Giovanni Rotondo, Italy
[4] TIGEM, Telethon Inst Genet & Med, I-80131 Naples, Italy
[5] Vanderbilt Univ, Dept Med, Div Med Genet, Nashville, TN 37232 USA
[6] Vanderbilt Univ, Dept Med, Div Nephrol, Nashville, TN 37232 USA
[7] Inst Human Genet, IL-52621 Tel Hashomer, Israel
[8] Dept Med C, IL-52621 Tel Hashomer, Israel
关键词
D O I
10.1093/hmg/10.4.305
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 (b(o,+)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 b(o,+)AT and affecting conserved amino acid residues with a small side chain generate a severe phenotype, while mutations in nonconserved 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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页码:305 / 316
页数:12
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