CLCN2 chloride channel mutations in familial hyperaldosteronism type II

Scholl, Ute I., 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 and Lifton, Richard P. (2018) CLCN2 chloride channel mutations in familial hyperaldosteronism type II. Nature Genetics, 1-6. doi:10.1038/s41588-018-0048-5

Author Scholl, Ute I.
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.
Title CLCN2 chloride channel mutations in familial hyperaldosteronism type II
Journal name Nature Genetics   Check publisher's open access policy
ISSN 1546-1718
Publication date 2018-02-05
Year available 2018
Sub-type Article (original research)
DOI 10.1038/s41588-018-0048-5
Open Access Status Not yet assessed
Start page 1
End page 6
Total pages 12
Place of publication New York, NY United States
Publisher Nature Publishing Group
Language eng
Subject 1311 Genetics
Abstract Primary aldosteronism, a common cause of severe hypertension 1 , 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.
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID P01 DK017433
U54 HG006504
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
UQ Diamantina Institute Publications
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Created: Wed, 14 Feb 2018, 11:11:07 EST