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

TLDR

Aldosterone‑producing adrenal adenomas cause severe hypertension by constitutive hormone production and uncontrolled cell proliferation, but the underlying mechanisms remain unclear. Somatic and inherited KCNJ5 mutations that increase Na⁺ conductance and depolarize adrenal cells were found in a subset of APAs, linking loss of K⁺ channel selectivity to excess aldosterone production, cell proliferation, and severe hypertension.

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 (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.