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

Citation
M. Font et al., Functional analysis of mutations in SLC7A9, and genotype-phenotype correlation in non-Type I cystinuria, HUM MOL GEN, 10(4), 2001, pp. 305-316
Citations number
38
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Molecular Biology & Genetics
Journal title
HUMAN MOLECULAR GENETICS
ISSN journal
0964-6906 → ACNP
Volume
10
Issue
4
Year of publication
2001
Pages
305 - 316
Database
ISI
SICI code
0964-6906(20010215)10:4<305:FAOMIS>2.0.ZU;2-4
Abstract
Cystinuria (OMIM 220100) is a common recessive disorder of renal reabsorpti on of cystine and dibasic amino acids that results in nephrolithiasis of cy stine, Mutations in SLC3A1, which encodes rBAT, cause Type I cystinuria, an d 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 SLC 7A9 (13 exons) and 28 new mutations in this gene that, together with the se ven previously reported, explain 79% of the alleles in 61 non-Type I cystin uria patients, These data demonstrate that SLC7A9 is the main non-Type I cy stinuria gene. Mutations G105R, V170M, A182T and R333W are the most frequen t SLC7A9 missense mutations found, Among heterozygotes carrying these mutat ions, A182T heterozygotes showed the lowest urinary excretion values of cys tine and dibasic amino acids, Functional analysis of mutation A182T after c o-expression with rBAT in HeLa cells revealed significant residual transpor t activity, In contrast, mutations G105R, V170M and R333W are associated to a complete or almost complete loss of transport activity, leading to a mor e severe urinary phenotype in heterozygotes. SLC7A9 mutations located in th e putative transmembrane domains of b(o,+)AT and affecting conserved amino acid residues with a small side chain generate a severe phenotype, while mu tations 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.