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

Item Type:Article
Title:A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism
Creators Name:Fernandes-Rosa, F.L. and Daniil, G. and Orozco, I.J. and Göppner, C. and El Zein, R. and Jain, V. and Boulkroun, S. and Jeunemaitre, X. and Amar, L. and Lefebvre, H. and Schwarzmayr, T. and Strom, T.M. and Jentsch, T.J. and Zennaro, M.C.
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-2Asp24 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.
Source:Nature Genetics
ISSN:1061-4036
Publisher:Nature Publishing Group (U.S.A.)
Volume:50
Number:3
Page Range:355-361
Date:March 2018
Official Publication:https://doi.org/10.1038/s41588-018-0053-8
PubMed:View item in PubMed

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