CLCN2 chloride channel mutations in familial hyperaldosteronism type II

Scholl, Ute I.; Yoo, Taekyeong; Kirchner, Marieluise; Gamble, Cory; Stölting, Gabriel; Stowasser, Michael; Fahlke, Christoph; Lash, Robert W.; Schewe, Julia; Chune, Gary; Nelson-Williams, Carol; McKenney, Daniel; Thiel, Anne; Untiet, Verena; Wu, Aihua; Choi, Jungmin; Gagliardi, Priscila; Jin, Sheng Chih; Loring, Erin; Choi, Murim; Gordon, Richard; Xu, Shengxin; Tan, Hua; Lifton, Richard P.; Onder, Ali Mirza; Mertins, Philipp; Jones, Deborah P.; Vichot, Alfred A.; Rump, Lars C.

doi:10.1038/s41588-018-0048-5

Journal Article

FZJ-2018-01170

CLCN2 chloride channel mutations in familial hyperaldosteronism type II

Scholl, U. I. (Corresponding author) ; Stölting, G.FZJ* ; Schewe, J. ; Thiel, A. ; Tan, H.FZJ* ; Nelson-Williams, C. ; Vichot, A. A. ; Jin, S. C. ; Loring, E. ; Untiet, V.FZJ* ; Yoo, T. ; Choi, J. ; Xu, S. ; Wu, A. ; Kirchner, M. ; Mertins, P. ; Rump, L. C. ; Onder, A. M. ; Gamble, C. ; McKenney, D. ; Lash, R. W. ; Jones, D. P. ; Chune, G. ; Gagliardi, P. ; Choi, M. ; Gordon, R. ; Stowasser, M. ; Fahlke, C.FZJ* ; Lifton, R. P.

2018
Nature America New York, NY

Nature genetics 50(3), 349-354 (2018) [10.1038/s41588-018-0048-5]

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Please use a persistent id in citations: doi:10.1038/s41588-018-0048-5

Abstract: 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.

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