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K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension

Murim Choi, Ute I Scholl, Peng Yue, Peyman Björklund, Bixiao Zhao, Carol Nelson-Williams, Weizhen Ji, Yoonsang Cho, Aniruddh Patel, Clara J Men, Elias Lolis, Max V Wisgerhof, David S Geller, Shrikant Mane, Per Hellman, Gunnar Westin, Göran Åkerström, Wenhui Wang, Tobias Carling, Richard P Lifton
Science 2011 February 11, 331 (6018): 768-72
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 (Ca(2+)) 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.


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