CLCN2 chloride channel mutations in familial hyperaldosteronism type II

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

doi:10.1038/s41588-018-0048-5

CLCN2 chloride channel mutations in familial hyperaldosteronism type II

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

93 Citations (Scopus)

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.

Original language	English
Journal	Nature Genetics
Volume	50
Issue number	3
Pages (from-to)	349-354
Number of pages	6
ISSN	1061-4036
DOIs	https://doi.org/10.1038/s41588-018-0048-5
Publication status	Published - 1 Mar 2018
Externally published	Yes

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Scholl, U. I., Stölting, G., Schewe, J., Thiel, A., Tan, H., Nelson-Williams, C., Vichot, A. A., Jin, S. C., Loring, E., Untiet, V., Yoo, T., Choi, J., Xu, S., Wu, A., Kirchner, M., Mertins, P., Rump, L. C., Onder, A. M., Gamble, C., ... Lifton, R. P. (2018). CLCN2 chloride channel mutations in familial hyperaldosteronism type II. Nature Genetics, 50(3), 349-354. https://doi.org/10.1038/s41588-018-0048-5

Scholl, UI, Stölting, G, Schewe, J, Thiel, A, Tan, H, Nelson-Williams, C, Vichot, AA, Jin, SC, Loring, E, Untiet, V, Yoo, T, Choi, J, Xu, S, Wu, A, Kirchner, M, Mertins, P, Rump, LC, Onder, AM, Gamble, C, McKenney, D, Lash, RW, Jones, DP, Chune, G, Gagliardi, P, Choi, M, Gordon, R, Stowasser, M, Fahlke, C & Lifton, RP 2018, 'CLCN2 chloride channel mutations in familial hyperaldosteronism type II', Nature Genetics, vol. 50, no. 3, pp. 349-354. https://doi.org/10.1038/s41588-018-0048-5

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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.",

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AU - Xu, Shengxin

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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

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AU - Stowasser, Michael

AU - Fahlke, Christoph

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N2 - 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.

AB - 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.

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CLCN2 chloride channel mutations in familial hyperaldosteronism type II

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