title: ClC-K chloride channels: emerging pathophysiology of Bartter syndrome type 3.
abstract: The mutations in the CLCNKB gene encoding the ClC-Kb chloride channel are responsible for Bartter syndrome type 3, one of the four variants of Bartter syndrome in the genetically based nomenclature. All forms of Bartter syndrome are characterized by hypokalemia, metabolic alkalosis, and secondary hyperaldosteronism, but Bartter syndrome type 3 has the most heterogeneous presentation, extending from severe to very mild. A relatively large number of CLCNKB mutations have been reported, including gene deletions and nonsense or missense mutations. However, only 20 CLCNKB mutations have been functionally analyzed, due to technical difficulties regarding ClC-Kb functional expression in heterologous systems. This review provides an overview of recent progress in the functional consequences of CLCNKB mutations on ClC-Kb chloride channel activity. It has been observed that 1) all ClC-Kb mutants have an impaired expression at the membrane; and 2) a minority of the mutants combines reduced membrane expression with altered pH-dependent channel gating. Although further investigation is needed to fully characterize disease pathogenesis, Bartter syndrome type 3 probably belongs to the large family of conformational diseases, in which the mutations destabilize channel structure, inducing ClC-Kb retention in the endoplasmic reticulum and accelerated channel degradation.
authors: UPMC Université Paris 06, UMR_S 1138, Team 3, Paris, France; INSERM, UMR_S 872, Paris, France;
authors: Olga
authors: O
authors: Andrini
authors: UPMC Université Paris 06, UMR_S 1138, Team 3, Paris, France; INSERM, UMR_S 872, Paris, France;
authors: Mathilde
authors: M
authors: Keck
authors: Department of Theoretical and Computational Biophysics, Max-Planck Institute for Biophysical Chemistry, Göttingen, Germany;
authors: Rodolfo
authors: R
authors: Briones
authors: UPMC Université Paris 06, UMR_S 1138, Team 3, Paris, France; INSERM, UMR_S 872, Paris, France;
authors: Stéphane
authors: S
authors: Lourdel
authors: Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Département de Génétique, Paris, France; and Université Paris-Descartes, Faculté de Médecine, Paris, France.
authors: Rosa
authors: R
authors: Vargas-Poussou
authors: UPMC Université Paris 06, UMR_S 1138, Team 3, Paris, France; INSERM, UMR_S 872, Paris, France; jacques.teulon@upmc.fr.
authors: Jacques
authors: J
authors: Teulon
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000235:genetics / Q000378:metabolism; D001477:Bartter Syndrome / Q000235:genetics*; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D004252:DNA Mutational Analysis / Q000379:methods; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation / Q000235:genetics*
chemical_list: D027321:Anion Transport Proteins; D018118:Chloride Channels
keywords: Bartter syndrome; CLC family of chloride transporters and channels; chloride channel