TY  - JOUR
AU  - Scholl, Ute I.
AU  - Stölting, Gabriel
AU  - Schewe, Julia
AU  - Thiel, Anne
AU  - Tan, Hua
AU  - Nelson-Williams, Carol
AU  - Vichot, Alfred A.
AU  - Jin, Sheng Chih
AU  - Loring, Erin
AU  - Untiet, Verena
AU  - Yoo, Taekyeong
AU  - Choi, Jungmin
AU  - Xu, Shengxin
AU  - Wu, Aihua
AU  - Kirchner, Marieluise
AU  - Mertins, Philipp
AU  - Rump, Lars C.
AU  - Onder, Ali Mirza
AU  - Gamble, Cory
AU  - McKenney, Daniel
AU  - Lash, Robert W.
AU  - Jones, Deborah P.
AU  - Chune, Gary
AU  - Gagliardi, Priscila
AU  - Choi, Murim
AU  - Gordon, Richard
AU  - Stowasser, Michael
AU  - Fahlke, Christoph
AU  - Lifton, Richard P.
TI  - CLCN2 chloride channel mutations in familial hyperaldosteronism type II
JO  - Nature genetics
VL  - 50
IS  - 3
SN  - 1546-1718
CY  - New York, NY
PB  - Nature America
M1  - FZJ-2018-01170
SP  - 349-354
PY  - 2018
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:29403011
UR  - <Go to ISI:>//WOS:000427933400009
DO  - DOI:10.1038/s41588-018-0048-5
UR  - https://juser.fz-juelich.de/record/843588
ER  -