CLCN2 chloride channel mutations in familial hyperaldosteronism type II

Nat Genet. 2018 Mar;50(3):349-354. doi: 10.1038/s41588-018-0048-5.

Ute I Scholl ¹ ², Gabriel Stölting ^# ³, Julia Schewe ^# ⁴, Anne Thiel ⁴, Hua Tan ³, Carol Nelson-Williams ⁵ ⁶, Alfred A Vichot ⁵ ⁶, Sheng Chih Jin ⁵, Erin Loring ⁵ ⁶ ⁷, Verena Untiet ³, Taekyeong Yoo ⁸, Jungmin Choi ⁵ ⁶, Shengxin Xu ⁹, Aihua Wu ⁹, Marieluise Kirchner ¹⁰, Philipp Mertins ¹⁰, Lars C Rump ⁴, Ali Mirza Onder ¹¹, Cory Gamble ¹², Daniel McKenney ¹³, Robert W Lash ¹⁴, Deborah P Jones ¹⁵, Gary Chune ¹⁶, Priscila Gagliardi ¹⁷, Murim Choi ⁸, Richard Gordon ⁹, Michael Stowasser ⁹, Christoph Fahlke ³, Richard P Lifton ⁵ ⁶ ⁷ ¹⁸

Affiliations

1 Department of Nephrology, Medical School, Heinrich Heine University Düsseldorf, Düsseldorf, Germany. ute.scholl@charite.de.
2 Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin Institute of Health, Berlin, Germany. ute.scholl@charite.de.
3 Institute of Complex Systems, Zelluläre Biophysik (ICS-4), Forschungszentrum Jülich, Jülich, Germany.
4 Department of Nephrology, Medical School, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
5 Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
6 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA.
7 Yale Center for Mendelian Genomics, New Haven, CT, USA.
8 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
9 Endocrine Hypertension Research Center, University of Queensland Diamantina Institute, Greenslopes and Princess Alexandra Hospitals, Brisbane, Queensland, Australia.
10 Proteomics Platform, Max Delbrück Center for Molecular Medicine in the Helmholtz Society and Core Unit of Proteomics, Berlin Institute of Health, Berlin, Germany.
11 Nephrology, Le Bonheur Children's Hospital, Memphis, TN, USA.
12 Cooper Clinic, PA, Fort Smith, AR, USA.
13 Peyton Manning Children's Hospital at St. Vincent, Indianapolis, IN, USA.
14 Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, MI, USA.
15 Division of Nephrology and Hypertension, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA.
16 Olin Teague Veterans Administration Hospital, Temple, TX, USA.
17 Division of Endocrinology, Nemours Children's Specialty Care, Jacksonville, FL, USA.
18 Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA.
# Contributed equally.

PMID: 29403011 DOI: 10.1038/s41588-018-0048-5

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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