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CLCN2chloride channel mutations in familial hyperaldosteronism type II
- Source :
- Nature Genetics; March 2018, Vol. 50 Issue: 3 p349-354, 6p
- Publication Year :
- 2018
-
Abstract
- Primary aldosteronism, a common cause of severe hypertension1 , 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 CLCN2variant found in the proband. CLCN2encodes 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. Whole-exome sequencing identifies mutations in CLCN2in individuals with familial hyperaldosteronism type II or early-onset primary aldosteronism. These gain-of-function mutations cause chloride channel opening and glomerulosa cell depolarization, showing a role for anion channels in aldosterone production.
Details
- Language :
- English
- ISSN :
- 10614036 and 15461718
- Volume :
- 50
- Issue :
- 3
- Database :
- Supplemental Index
- Journal :
- Nature Genetics
- Publication Type :
- Periodical
- Accession number :
- ejs44927882
- Full Text :
- https://doi.org/10.1038/s41588-018-0048-5