A founder mutation in the CLCNKB gene causes Bartter syndrome type III in Spain.

The term "Bartter syndrome" encompasses a group of closely related inherited tubulopathies characterized by markedly reduced NaCl transport by the distal nephron. At present, five different genetic variants have been demonstrated. The majority of patients with so-called classic Bartter syndrome carry inactivating mutations of the CLCNKB gene encoding the basolateral ClC-Kb chloride channel (Bartter syndrome type III). The purpose of this study was to investigate the underlying mutation in cases of classic Bartter syndrome followed at our center. Ten patients, including two sisters, with clinical and biochemical features of classic Bartter syndrome were included in the mutational analysis. They originated from different regions of Spain with either Basque or Spanish ancestry. There was no history of consanguineous marriage in any of the kindreds. The parents and siblings of each patient, as well as a population of 300 healthy control adult subjects, were also analyzed. All ten patients were found to be homozygous for an identical missense mutation in the CLCNKB gene, substituting a threonine for an alanine at codon 204 (A204T) in the putative fifth transmembrane domain of the protein. None of the 300 control subjects were homozygous for the A204T allele. Overall, the A204T mutation was detected on 2/600 control chromosomes. Despite sharing a common mutation, the clinical manifestations of the syndrome in the patients varied from lack of symptoms to severe growth retardation. Demonstration of a point mutation within the CLCNKB gene as the apparently unique cause of Bartter syndrome type III in Spain is highly suggestive of a founder effect. Our results also support the lack of correlation between genotype and phenotype in this disease.