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

Research output: Contribution to journalArticlepeer-review

102 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 languageEnglish
Pages (from-to)349-354
Number of pages6
JournalNature Genetics
Volume50
Issue number3
DOIs
Publication statusPublished - 2018 Mar 1
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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