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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., 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
Publisher:Nature Publishing Group
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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