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Science 331 (6018): 768-772

Copyright © 2011 by the American Association for the Advancement of Science

K+ Channel Mutations in Adrenal Aldosterone-Producing Adenomas and Hereditary Hypertension

Murim Choi,1 Ute I. Scholl,1 Peng Yue,2,* Peyman Björklund,3,4,* Bixiao Zhao,1,* Carol Nelson-Williams,1 Weizhen Ji,1 Yoonsang Cho,5 Aniruddh Patel,1 Clara J. Men,1 Elias Lolis,5 Max V. Wisgerhof,6 David S. Geller,7 Shrikant Mane,8 Per Hellman,4 Gunnar Westin,4 Göran Åkerström,4 Wenhui Wang,2 Tobias Carling,3 Richard P. Lifton1,{dagger}

Abstract: Endocrine tumors such as aldosterone-producing adrenal adenomas (APAs), a cause of severe hypertension, feature constitutive hormone production and unrestrained cell proliferation; the mechanisms linking these events are unknown. We identify two recurrent somatic mutations in and near the selectivity filter of the potassium (K+) channel KCNJ5 that are present in 8 of 22 human APAs studied. Both produce increased sodium (Na+) conductance and cell depolarization, which in adrenal glomerulosa cells produces calcium (Ca2+) entry, the signal for aldosterone production and cell proliferation. Similarly, we identify an inherited KCNJ5 mutation that produces increased Na+ conductance in a Mendelian form of severe aldosteronism and massive bilateral adrenal hyperplasia. These findings explain pathogenesis in a subset of patients with severe hypertension and implicate loss of K+ channel selectivity in constitutive cell proliferation and hormone production.

1 Departments of Genetics and Internal Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
2 Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
3 Department of Surgery, Yale Endocrine Neoplasia Laboratory and Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510, USA.
4 Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
5 Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA.
6 Division of Endocrinology, Henry Ford Hospital, Detroit, MI 48202, USA.
7 Section of Nephrology, Yale University School of Medicine, and Department of Medicine, Veterans Affairs Medical Center, West Haven, CT 06516, USA.
8 Yale Center for Genome Analysis, Yale University School of Medicine, West Haven, CT 06516, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed: E-mail: richard.lifton{at}yale.edu


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