A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism

Nat Genet. 2018 Mar;50(3):355-361. doi: 10.1038/s41588-018-0053-8.

Fabio L Fernandes-Rosa ^# ¹ ² ³, Georgios Daniil ^# ⁴ ⁵, Ian J Orozco ^# ⁶ ⁷, Corinna Göppner ⁶ ⁷, Rami El Zein ⁴ ⁵, Vandana Jain ⁸, Sheerazed Boulkroun ⁴ ⁵, Xavier Jeunemaitre ⁴ ⁵ ⁹, Laurence Amar ⁴ ⁵ ¹⁰, Hervé Lefebvre ¹¹ ¹² ¹³, Thomas Schwarzmayr ¹⁴, Tim M Strom ¹⁴ ¹⁵, Thomas J Jentsch ¹⁶ ¹⁷, Maria-Christina Zennaro ¹⁸ ¹⁹ ²⁰

Affiliations

1 INSERM, UMRS 970, Paris Cardiovascular Research Center, Paris, France. fabio.fernandes-rosa@inserm.fr.
2 Université Paris Descartes, Sorbonne Paris Cité, Paris, France. fabio.fernandes-rosa@inserm.fr.
3 Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France. fabio.fernandes-rosa@inserm.fr.
4 INSERM, UMRS 970, Paris Cardiovascular Research Center, Paris, France.
5 Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
6 Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany.
7 Max Delbrück Centrum für Molekulare Medizin (MDC), Berlin, Germany.
8 Division of Pediatric Endocrinology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
9 Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France.
10 Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Unité Hypertension Artérielle, Paris, France.
11 Normandie Université, UNIROUEN, Rouen, France.
12 INSERM, DC2N, Rouen, France.
13 Department of Endocrinology, Diabetes and Metabolic Diseases, University Hospital of Rouen, Rouen, France.
14 Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
15 Institute of Human Genetics, Technische Universität München, Munich, Germany.
16 Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany. jentsch@fmp-berlin.de.
17 Max Delbrück Centrum für Molekulare Medizin (MDC), Berlin, Germany. jentsch@fmp-berlin.de.
18 INSERM, UMRS 970, Paris Cardiovascular Research Center, Paris, France. maria-christina.zennaro@inserm.fr.
19 Université Paris Descartes, Sorbonne Paris Cité, Paris, France. maria-christina.zennaro@inserm.fr.
20 Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France. maria-christina.zennaro@inserm.fr.
# Contributed equally.

PMID: 29403012 DOI: 10.1038/s41588-018-0053-8

Abstract

Primary aldosteronism is the most common and curable form of secondary arterial hypertension. We performed whole-exome Sequencing in patients with early-onset primary aldosteronism and identified a de novo heterozygous c.71G>A/p.Gly24Asp mutation in the CLCN2 gene, encoding the voltage-gated ClC-2 Chloride Channel ¹ , in a patient diagnosed at 9 years of age. Patch-clamp analysis of glomerulosa cells of mouse adrenal gland slices showed hyperpolarization-activated Cl^- currents that were abolished in Clcn2^-/- mice. The p.Gly24Asp variant, located in a well-conserved 'inactivation domain'^2,3, abolished the voltage- and time-dependent gating of ClC-2 and strongly increased Cl^- conductance at resting potentials. Expression of ClC-2^Asp24 in adrenocortical cells increased expression of aldosterone synthase and aldosterone production. Our data indicate that CLCN2 mutations cause primary aldosteronism. They highlight the important role of chloride in aldosterone biosynthesis and identify ClC-2 as the foremost chloride conductor of resting glomerulosa cells.

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