title: Analysis of the genes SLC7A9 and SLC3A1 in unclassified cystinurics: mutation detection rates and association between variants in SLC7A9 and the disease.
abstract: Cystinuria is a common inherited disorder of defective renal reabsorption of cystine and dibasic amino acids. Recently, 2 responsible genes have been identified: mutations in the SLC3AI gene encoding the glycoprotein rBAT cause cystinuria type I, while variants in the SLC7A9 gene have been demonstrated in non-type I cystinuria; its gene product b(0)+AT is the light chain of the renal cystine transport system rBAT/b(0),+-AT. To estimate the role of both genes in the etiology of cystinuria, we searched for sequence alterations in SLC7A9 and SLC3AI: 30 unclassified cystinurics were investigated. In 50% of patients (15/30), point mutations in SLC3A1 were detected. Screening of the SLC7A9 gene revealed 10 mutations in 8 patients corresponding to a frequency of 27%. In addition to previously published mutations in the SLC7A9 gene, we detected 2 new mutations (F 140S, c747delG). An overall detection rate of 73% (22/30) in unclassified patients is delineated for mutations in both genes. In 33% (10/30), 2 mutations were detected, in 40% (12/30) 1 mutation. Furthermore, 5 new polymorphic sites were identified in SLC7A9. While the base pair variation in intron 9 is homogeneously distributed in patients and control individuals, the allelic and genotypic distributions of the polymorphisms in 3 exons of SLC7A9--exons 2, 5 and 6--and intron 3 differ significantly between both groups. Our results suggest that some haplotypes defined through the exons 2, 5 and 6 and intron 3 might be markers of a functional variant in the SLC7A9 gene. Evidently, since the mutation detection rates in the 2 so far known cystinuria genes never reach 100%, further genes and modulating factors should influence the phenotype in a subset of patients. However, the presented data show that testing for mutations in the 2 currently known cystinuria genes is already a meaningful approach to the molecular diagnostics of the disease.
authors.affiliation: Institute of Human Genetics, Technical University of Aachen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Schmidt
authors.forename: A
authors.initials: A
authors.lastname: Albers
authors.forename: J
authors.initials: J
authors.lastname: Tomiuk
authors.forename: K
authors.initials: K
authors.lastname: Eggermann
authors.forename: C
authors.initials: C
authors.lastname: Wagner
authors.forename: G
authors.initials: G
authors.lastname: Capasso
authors.forename: S
authors.initials: S
authors.lastname: Lahme
authors.forename: A
authors.initials: A
authors.lastname: Hesse
authors.forename: F
authors.initials: F
authors.lastname: Lang
authors.forename: K
authors.initials: K
authors.lastname: Zerres
authors.forename: T
authors.initials: T
authors.lastname: Eggermann
mesh_terms: D026923:Amino Acid Transport Systems, Basic; D002352:Carrier Proteins / Q000235:genetics*; D003555:Cystinuria / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005787:Gene Frequency; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007438:Introns / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics*; D017354:Point Mutation; D011110:Polymorphism, Genetic
chemical_list: D026923:Amino Acid Transport Systems, Basic; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; C499489:SLC7A9 protein, human