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| Item Type: | Article |
|---|---|
| Title: | CLCN2 chloride channel mutations in familial hyperaldosteronism type II |
| Creators: |
Scholl, U.I.  ORCID: https://orcid.org/0000-0002-0309-8045, Stölting, G. ORCID: https://orcid.org/0000-0002-2339-0545, Schewe, J., Thiel, A. ORCID: https://orcid.org/0000-0002-9523-2351, Tan, H., Nelson-Williams, C. ORCID: https://orcid.org/0000-0003-0768-4751, Vichot, A.A., Jin, S.C., Loring, E., Untiet, V. ORCID: https://orcid.org/0000-0002-1888-6378, Yoo, T., Choi, J., Xu, S., Wu, A., Kirchner, M. ORCID: https://orcid.org/0000-0002-7049-534X, Mertins, P. ORCID: https://orcid.org/0000-0002-2245-528X, Rump, L.C., Onder, A.M., Gamble, C., McKenney, D., Lash, R.W., Jones, D.P., Chune, G., Gagliardi, P., Choi, M. ORCID: https://orcid.org/0000-0002-9195-1455, Gordon, R., Stowasser, M., Fahlke, C. and Lifton, R.P.
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| 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 |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Volume: | 50 |
| Number: | 3 |
| 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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