Background: To investigate the genetic cause of inherited hypokalemic metabolic alkalosis associated with Gitelman's syndrome, we searched for mutations in the SLC12A3 gene (thiazide-sensitive NaCl cotransporter) among a set of patients from the Czech Republic and Slovakia.
Methods: We collected blood samples of patients from 16 families with characteristic clinical features. DNA was analyzed for mutation detection with SSCP and subsequent sequencing. Several mutations might be missed when only the SSCP method is applied, therefore direct sequencing of all the 26 exons became an essential tool.
Results: Genetic analysis revealed mainly missense mutations. Two novel mutations, c.480dupC (p.Pro160fsX97) and c.238dupCC (p. Pro79fsX35), caused a frameshift and preliminary stop codon appearance. Missense mutation c.790 G --> C (p.Gly264Arg) has never been reported before. Mutation c.1315G --> A (p.Gly439Ser) was frequent among our collection of unrelated patients (5 out of 16). Homozygous Gly439Ser was observed in a patient with chondrocalcinosis.
Conclusion: We identified 13 different causative mutations in a cohort of Gitelman syndrome patients. Three of those mutations are novel. The occurrence of two mutation detections per individual corresponding to a recessive trait of inheritance was 62.5%. Gly439Ser is the most frequent type of mutation among our patients. Statistic evaluation of genotype/phenotype correlation could not be carried out.
Copyright 2006 S. Karger AG, Basel.