CLCN2 chloride channel mutations in familial hyperaldosteronism type II.

TitleCLCN2 chloride channel mutations in familial hyperaldosteronism type II.
Publication TypeJournal Article
Year of Publication2018
AuthorsScholl, UI, Stölting, G, Schewe, J, Thiel, A, Tan, H, Nelson-Williams, C, Vichot, AA, Jin, SChih, Loring, E, Untiet, V, Yoo, T, Choi, J, Xu, S, Wu, A, Kirchner, M, Mertins, P, Rump, LC, Onder, AMirza, Gamble, C, McKenney, D, Lash, RW, Jones, DP, Chune, G, Gagliardi, P, Choi, M, Gordon, R, Stowasser, M, Fahlke, C, Lifton, RP
JournalNat Genet
Date Published2018 Mar

Primary aldosteronism, a common cause of severe hypertension , features constitutive production of the adrenal steroid aldosterone. We analyzed a multiplex family with familial hyperaldosteronism type II (FH-II) 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.

Alternate JournalNat. Genet.
PubMed ID29403011
PubMed Central IDPMC5862758
Grant ListUM1 HG006504 / HG / NHGRI NIH HHS / United States
UL1 TR001863 / TR / NCATS NIH HHS / United States
S10 OD018521 / OD / NIH HHS / United States
T32 DK007276 / DK / NIDDK NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
P01 DK017433 / DK / NIDDK NIH HHS / United States