Paper of the Month
FEBRUARY 2018 – CLCN2 chloride channel mutations in familial hyperaldosteronism type II
In February Ute Scholl receives the Paper of the Month award.
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. CLCN2 chloride channel mutations in familial hyperaldosteronism type II. Nature Genetics 2018. DOI: 10.1038/s41588-018-0048-5
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.