@article{955181a068e44d6a953e4fd85c615869,
title = "CLCN2 chloride channel mutations in familial hyperaldosteronism type II",
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.",
author = "Scholl, {Ute I.} and Gabriel St{\"o}lting and Julia Schewe and Anne Thiel and Hua Tan and Carol Nelson-Williams and Vichot, {Alfred A.} and Jin, {Sheng Chih} and Erin Loring and Verena Untiet and Taekyeong Yoo and Jungmin Choi and Shengxin Xu and Aihua Wu and Marieluise Kirchner and Philipp Mertins and Rump, {Lars C.} and Onder, {Ali Mirza} and Cory Gamble and Daniel McKenney and Lash, {Robert W.} and Jones, {Deborah P.} and Gary Chune and Priscila Gagliardi and Murim Choi and Richard Gordon and Michael Stowasser and Christoph Fahlke and Lifton, {Richard P.}",
note = "Funding Information: We thank our patients and their families for their invaluable contributions, the Yale Center for Genome Analysis for next-generation sequencing, the Center for Advanced Imaging (CAi) at Heinrich Heine University for providing a confocal microscope, S. Weidtkamp-Peters and S. H{\"a}nsch for technical assistance, J. Zhang for helpful discussions, E. Seidel, N. Erlenhardt and N. Kl{\"o}cker for providing immunoprecipitation protocols and helpful discussions, C. Gomez-Sanchez (University of Mississippi) for providing plasmids, W. Rainey (University of Michigan) for providing HAC15 cells and M. Haase (Heinrich Heine University D{\"u}sseldorf) for providing H295R cells. Computational support and infrastructure were in part provided by the Centre for Information and Media Technology (D{\"u}sseldorf). This study was supported in part by the Ministerium f{\"u}r Kultur und Wissenschaft des Landes Nordrhein-Westfalen (R{\"u}ckkehrprogramm and Junges Kolleg) and the Deutsche Forschungsgemeinschaft (SCHO 1386/2-1) (all to U.I.S.) and the NIH Center for Mendelian Genomics (5U54HG006504), NIH P01DK17433 and the Howard Hughes Medical Institute (all to R.P.L.). Funding Information: We thank our patients and their families for their invaluable contributions, the Yale Center for Genome Analysis for next-generation sequencing, the Center for Advanced Imaging (CAi) at Heinrich Heine University for providing a confocal microscope, S. Weidtkamp-Peters and S. Hnsch for technical assistance, J. Zhang for helpful discussions, E. Seidel, N. Erlenhardt and N. Klcker for providing immunoprecipitation protocols and helpful discussions, C. Gomez-Sanchez (University of Mississippi) for providing plasmids, W. Rainey (University of Michigan) for providing HAC15 cells and M. Haase (Heinrich Heine University Dsseldorf) for providing H295R cells. Computational support and infrastructure were in part provided by the Centre for Information and Media Technology (Dsseldorf). This study was supported in part by the Ministerium f?r Kultur und Wissenschaft des Landes Nordrhein-Westfalen (Rckkehrprogramm and Junges Kolleg) and the Deutsche Forschungsgemeinschaft (SCHO 1386/2-1) (all to U.I.S.) and the NIH Center for Mendelian Genomics (5U54HG006504), NIH P01DK17433 and the Howard Hughes Medical Institute (all to R.P.L.). Publisher Copyright: {\textcopyright} 2018 The Author(s).",
year = "2018",
month = mar,
day = "1",
doi = "10.1038/s41588-018-0048-5",
language = "English",
volume = "50",
pages = "349--354",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "3",
}