ClC-K chloride channels: emerging pathophysiology of Bartter syndrome type 3

Author:

Andrini Olga12,Keck Mathilde12,Briones Rodolfo3,Lourdel Stéphane12,Vargas-Poussou Rosa45,Teulon Jacques12

Affiliation:

1. UPMC Université Paris 06, UMR_S 1138, Team 3, Paris, France;

2. INSERM, UMR_S 872, Paris, France;

3. Department of Theoretical and Computational Biophysics, Max-Planck Institute for Biophysical Chemistry, Göttingen, Germany;

4. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Département de Génétique, Paris, France; and

5. Université Paris-Descartes, Faculté de Médecine, Paris, France

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.

Funder

Agence Nationale de la Recherche (L' Agence Nationale de la Recherche)

ECOS-sud

Fondation du rein

Deutsche Forschungsgemeinschaft (DFG)

Publisher

American Physiological Society

Subject

Physiology

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