Journal Article

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

Geller, David S, Zhao, Bixiao, Choi, Murim, Wang, Wenhui, Ji, Weizhen, Mane, Shrikant, Björklund, Peyman, Westin, Gunnar, Lolis, Elias, Lifton, Richard P, Yue, Peng, Cho, Yoonsang, Wisgerhof, Max V, Carling, Tobias, Hellman, Per, Scholl, Ute I, Patel, Aniruddh, Åkerström, Göran, Men, Clara J, Nelson-Williams, Carol

2011

Overview

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.

• Publisher: American Association for the Advancement of Science
• Subject: Adenoma / Adrenal Cortex Neoplasms - genetics / Adrenal Cortex Neoplasms - metabolism / Adrenal Cortex Neoplasms - pathology / Adrenal Glands - pathology / Adrenocortical Adenoma - genetics / Adrenocortical Adenoma - metabolism / Adrenocortical Adenoma - pathology / aldosterone / Aldosterone - metabolism / Biological and medical sciences / calcium / Cell growth / Cell Line / Cell physiology / Cell Proliferation / Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes / Classical genetics, quantitative genetics, hybrids / Depolarization / Female / Fundamental and applied biological sciences. Psychology / G Protein-Coupled Inwardly-Rectifying Potassium Channels - chemistry / G Protein-Coupled Inwardly-Rectifying Potassium Channels - genetics / G Protein-Coupled Inwardly-Rectifying Potassium Channels - metabolism / Genetic mutation / Genetics of eukaryotes. Biological and molecular evolution / Human / Humans / Hyperaldosteronism / Hyperaldosteronism - genetics / Hyperaldosteronism - metabolism / Hyperaldosteronism - pathology / Hyperplasia / Hypertension / Hypertension - genetics / Hypertension - metabolism / Loss of heterozygosity / Male / MEDICIN / MEDICINE / Molecular and cellular biology / Mutant Proteins - chemistry / Mutant Proteins - genetics / Mutant Proteins - metabolism / Mutation / neoplasms / pathogenesis / patients / potassium / Potassium - metabolism / potassium channels / Protein Multimerization / Sequencing / sodium / Sodium - metabolism / Somatic mutation / Tumors / Zona Glomerulosa - metabolism / Zona Glomerulosa - pathology