26 February 2003
Background: Gitelman’s syndrome (GS) is characterized by hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria and these phenotypic features have been shown to be attributable to mutations in the gene encoding the thiazide-sensitive Na/Cl cotransporter (NCCT). Until now, 55 different mutations have been reported and most of the families affected with GS exhibit autosomal recessive inheritance. Methods: All 26 exons of the human NCCT gene were investigated in 2 German NCCT-deficient patients and their families. Mutation detection was performed by either direct automated sequencing of polymerase chain reaction (PCR)-amplified DNA products or by sequence analysis of cloned PCR products. Results: In a 47-year-old German GS female a novel non-conservative missense mutation (S314F) and a complex deletion/insertion in the NCCT gene were found to be associated with the disorder. A further novel non-conservative substitution (S402F) together with a frequently observed R209W exchange were found in a 19-year-old German GS female. Conclusions: The observation of a compound heterozygote state in both females affected and the absence of a GS phenotype in their relatives carrying a single mutant allele is consistent with an autosomal recessive pattern of inheritance.