CLCN2 chloride channel mutations in familial hyperaldosteronism type II

Item Type:	Article
Title:	CLCN2 chloride channel mutations in familial hyperaldosteronism type II
Creators Name:	Scholl, U.I. and Stölting, G. and Schewe, J. and Thiel, A. and Tan, H. and Nelson-Williams, C. and Vichot, A.A. and Jin, S.C. and Loring, E. and Untiet, V. and Yoo, T. and Choi, J. and Xu, S. and Wu, A. and Kirchner, M. and Mertins, P. and Rump, L.C. and Onder, A.M. and Gamble, C. and McKenney, D. and Lash, R.W. and Jones, D.P. and Chune, G. and Gagliardi, P. and Choi, M. and Gordon, R. and Stowasser, M. and Fahlke, C. and Lifton, R.P.
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.
Keywords:	Adrenal Glands, Amino Acid Sequence, Chloride Channels, Cohort Studies, DNA Mutational Analysis, Hyperaldosteronism, Mutation, Pedigree
Source:	Nature Genetics
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Volume:	50
Number:	3
Page Range:	349-354
Date:	March 2018
Official Publication:	https://doi.org/10.1038/s41588-018-0048-5
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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