Details

Autor(en) / Beteiligte

• 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

Titel

CLCN2 chloride channel mutations in familial hyperaldosteronism type II

Ist Teil von

• Nature genetics, 2018-03, Vol.50 (3), p.349-354

Ort / Verlag

United States: Nature Publishing Group

Erscheinungsjahr

2018

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.