%0 Journal Article
%A Scholl, Ute I.
%A Stölting, Gabriel
%A Schewe, Julia
%A Thiel, Anne
%A Tan, Hua
%A Nelson-Williams, Carol
%A Vichot, Alfred A.
%A Jin, Sheng Chih
%A Loring, Erin
%A Untiet, Verena
%A Yoo, Taekyeong
%A Choi, Jungmin
%A Xu, Shengxin
%A Wu, Aihua
%A Kirchner, Marieluise
%A Mertins, Philipp
%A Rump, Lars C.
%A Onder, Ali Mirza
%A Gamble, Cory
%A McKenney, Daniel
%A Lash, Robert W.
%A Jones, Deborah P.
%A Chune, Gary
%A Gagliardi, Priscila
%A Choi, Murim
%A Gordon, Richard
%A Stowasser, Michael
%A Fahlke, Christoph
%A Lifton, Richard P.
%T CLCN2 chloride channel mutations in familial hyperaldosteronism type II
%J Nature genetics
%V 50
%N 3
%@ 1546-1718
%C New York, NY
%I Nature America
%M FZJ-2018-01170
%P 349-354
%D 2018
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:29403011
%U <Go to ISI:>//WOS:000427933400009
%R 10.1038/s41588-018-0048-5
%U https://juser.fz-juelich.de/record/843588