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

M Choi, UI Scholl, P Yue, P Björklund, B Zhao… - Science, 2011 - science.org
M Choi, UI Scholl, P Yue, P Björklund, B Zhao, C Nelson-Williams, W Ji, Y Cho, A Patel
Science, 2011science.org
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 …
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.
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