CLCN2 chloride channel mutations in familial hyperaldosteronism type II

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.; McKenney, D.; Lash, R.W.; Jones, D.P.; Chune, G.; Gagliardi, P.; Choi, M.; Gordon, R.; Stowasser, M.; Fahlke, C.; Lifton, R.P.

CLCN2 chloride channel mutations in familial hyperaldosteronism type II

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Item Type:	Article
Title:	CLCN2 chloride channel mutations in familial hyperaldosteronism type II
Creators Name:	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., McKenney, D., Lash, R.W., Jones, D.P., Chune, G., Gagliardi, P., Choi, M., Gordon, R., Stowasser, M., 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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