Description: CLCN2 chloride channel mutations in familial hyperaldosteronism type II

This title appears in the Scientific Report : 2018

CLCN2 chloride channel mutations in familial hyperaldosteronism type II

Primary aldosteronism, a common cause of severe hypertension1, features constitutive production of the adrenal steroid aldosterone. We analyzed a multiplex family with familial hyperaldosteronism type II (FH-II)2 and 80 additional probands with unsolved early-onset primary aldosteronism. Eight proba...

Personal Name(s):	Scholl, Ute I. (Corresponding author)
	Stölting, Gabriel / Schewe, Julia / Thiel, Anne / Tan, Hua / Nelson-Williams, Carol / Vichot, Alfred A. / Jin, Sheng Chih / Loring, Erin / Untiet, Verena / Yoo, Taekyeong / Choi, Jungmin / Xu, Shengxin / Wu, Aihua / Kirchner, Marieluise / Mertins, Philipp / Rump, Lars C. / Onder, Ali Mirza / Gamble, Cory / McKenney, Daniel / Lash, Robert W. / Jones, Deborah P. / Chune, Gary / Gagliardi, Priscila / Choi, Murim / Gordon, Richard / Stowasser, Michael / Fahlke, Christoph / Lifton, Richard P.
Contributing Institute:	Zelluläre Biophysik; ICS-4
Published in:	Nature genetics, 50 (2018) 3, S. 349-354
Imprint:	New York, NY Nature America 2018
DOI:	10.1038/s41588-018-0048-5
PubMed ID:	29403011
Document Type:	Journal Article
Research Program:	Physical Basis of Diseases
	Publikationsportal JuSER

Please use the identifier: http://dx.doi.org/10.1038/s41588-018-0048-5 in citations.

Primary aldosteronism, a common cause of severe hypertension1, features constitutive production of the adrenal steroid aldosterone. We analyzed a multiplex family with familial hyperaldosteronism type II (FH-II)2 and 80 additional probands with unsolved early-onset primary aldosteronism. Eight probands had novel heterozygous variants in CLCN2, including two de novo mutations and four independent occurrences of a mutation encoding an identical p.Arg172Gln substitution; all relatives with early-onset primary aldosteronism carried the CLCN2 variant found in the proband. CLCN2 encodes a voltage-gated chloride channel expressed in adrenal glomerulosa that opens at hyperpolarized membrane potentials. Channel opening depolarizes glomerulosa cells and induces expression of aldosterone synthase, the rate-limiting enzyme for aldosterone biosynthesis. Mutant channels show gain of function, with higher open probabilities at the glomerulosa resting potential. These findings for the first time demonstrate a role of anion channels in glomerulosa membrane potential determination, aldosterone production and hypertension. They establish the cause of a substantial fraction of early-onset primary aldosteronism.