The population-specific distribution and frequencies of genomic variants in the SLC3A1 and SLC7A9 genes and their application in molecular genetic testing of cystinuria.
Cystinuria is a common inherited aminoaciduria resulting in nephrolithiasis. Mutations in two genes, SLC3A1 and SLC7A9, have been identified in cystinuric patients. Considering the population-specific distribution of genetic variants in the SLC3A1 gene, we focused our study on mutations in SLC3A1 and SLC7A9 described more than once in the literature. We evaluated the usefulness of this restricted analysis as a diagnostic approach. Furthermore, the data obtained were used to estimate the frequency of heterozygote carriers of SLC3A1 mutations in the general European population. A total of 22 unclassified cystinuric patients were screened for genetic variants in four exons of both SLC3A1 and SLC7A9 in which the most common mutations have been identified. For screening, we used single strand conformation polymorphism analysis (SSCP), restriction assays, real-time PCR and direct sequencing. In total, we identified mutations in 17 of our 22 patients, including a new mutation (R365Q) as well as a novel polymorphism (c.1035G/A) within the SLC3A1 gene. An ethnic influence on the distribution of mutations was confirmed: T216M in SLC3A1 is the major mutation in south-eastern Europe, whereas M467T in SLC3A1 is mainly found in western Europe. A complex duplication in SLC3A1 is restricted to German patients. Generally, we could show that a stepwise analysis directed to the most common mutations in the two cystinuria genes is sufficient to detect variants in more than 75% of patients of European origin. The test consists of nine different PCR-based approaches and therefore represents a low-cost, reliable and timesaving diagnostic tool.
Institute of Human Genetics, Aachen University Hospital, Pauwelsstrasse 30, 52074 Aachen, Germany.
Christa
C
Schmidt
Udo
U
Vester
Albrecht
A
Hesse
Sven
S
Lahme
Florian
F
Lang
Klaus
K
Zerres
Thomas
T
Eggermann
D026923:Amino Acid Transport Systems, Basic / Q000235:genetics*; D001483:Base Sequence; D027682:Cation Transport Proteins / Q000235:genetics*; D000079923:Copper Transporter 1; D003555:Cystinuria / Q000208:ethnology* / Q000235:genetics*; D005091:Exons; D005787:Gene Frequency; D005820:Genetic Testing; D014644:Genetic Variation; D005828:Genetics, Population / Q000706:statistics & numerical data*; D015894:Genome, Human; D005858:Germany; D006579:Heterozygote; D006801:Humans; D007438:Introns; D009154:Mutation; D018807:Polymorphism, Single-Stranded Conformational; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
D026923:Amino Acid Transport Systems, Basic; D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; C490079:SLC31A1 protein, human; C499489:SLC7A9 protein, human