CLCN2 chloride channel mutations in familial hyperaldosteronism type II
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CLCN2 chloride channel mutations in familial hyperaldosteronism type II. / Scholl, Ute I; Stölting, Gabriel; Schewe, Julia; Thiel, Anne; Tan, Hua; Nelson-Williams, Carol; Vichot, Alfred A; Jin, Sheng Chih; Loring, Erin; Untiet, Verena; Yoo, Taekyeong; Choi, Jungmin; Xu, Shengxin; Wu, Aihua; Kirchner, Marieluise; Mertins, Philipp; Rump, Lars C; Onder, Ali Mirza; Gamble, Cory; McKenney, Daniel; Lash, Robert W; Jones, Deborah P; Chune, Gary; Gagliardi, Priscila; Choi, Murim; Gordon, Richard; Stowasser, Michael; Fahlke, Christoph; Lifton, Richard P.
In: Nature Genetics, Vol. 50, No. 3, 2018, p. 349-354.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - CLCN2 chloride channel mutations in familial hyperaldosteronism type II
AU - Scholl, Ute I
AU - Stölting, Gabriel
AU - Schewe, Julia
AU - Thiel, Anne
AU - Tan, Hua
AU - Nelson-Williams, Carol
AU - Vichot, Alfred A
AU - Jin, Sheng Chih
AU - Loring, Erin
AU - Untiet, Verena
AU - Yoo, Taekyeong
AU - Choi, Jungmin
AU - Xu, Shengxin
AU - Wu, Aihua
AU - Kirchner, Marieluise
AU - Mertins, Philipp
AU - Rump, Lars C
AU - Onder, Ali Mirza
AU - Gamble, Cory
AU - McKenney, Daniel
AU - Lash, Robert W
AU - Jones, Deborah P
AU - Chune, Gary
AU - Gagliardi, Priscila
AU - Choi, Murim
AU - Gordon, Richard
AU - Stowasser, Michael
AU - Fahlke, Christoph
AU - Lifton, Richard P
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
U2 - 10.1038/s41588-018-0048-5
DO - 10.1038/s41588-018-0048-5
M3 - Journal article
C2 - 29403011
VL - 50
SP - 349
EP - 354
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 3
ER -
ID: 209898480