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

Abstract

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.

Aplicação da biologia molecular na abordagem da síndrome de Bartter: relato de caso

“…Therefore, although not widely available in Brazil, molecular tools have become increasingly important for the diagnosis of BS. 2,5,6,9 The rational use of molecular biology techniques will certainly improve our understanding of the genetic aspects of BS, allowing an individualized approach to our patients.…”

“…2,5,6,9,12 The recent study by Brochard et al,2 who investigated mutations in 42 children with BS, is worth mentioning. Most of those children had heterozygous mutations of the KCNJ1 gene (45%).…”

“…[2][3][4][5] Because their diagnosis is frequently delayed, BS patients are inadequately managed for long periods, with the development of nephrocalcinosis and even end-stage chronic kidney disease (CKD). 9 We report two sisters diagnosed with BS, highlighting the importance of genetic characterization for a definitive diagnosis. We also propose a flow chart for the rational use of molecular biology techniques for BS diagnosis.…”

“…2,7 Changes in the chloride channel Kb (CLCNKB) gene, which encodes CLC-Kb, reduce channel activity, producing BS type III, which is associated with significant salt loss and hypokalemia. 8,9 BS type IV has a prenatal presentation consisting of sensorineural deafness and early renal failure. 10 It is chiefly caused by mutations of the Bartter syndrome, infantile, with sensorineural deafness (BSND) gene, which encodes bartin, a protein modulating stability, superficial cellular location and function of the CIC-Ka and CIC-Kb channels.…”

A Spanish Founder Mutation in the Chloride Channel Gene, <i>CLCNKB</i>, as a Cause of Atypical Bartter Syndrome in Adult Age

“…Recently, Rodriguez-Soriano et al [12] have reported a homozygous A204T missense mutation in the CLCNKB gene in 10 Spanish patients with clinical and biochemical features of cBS. This mutation has only been detected in Spain and its presence in families from different geographic regions and different ethnic origins suggests a founder effect in the Spanish population.…”