title: K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary 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.
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Murim
authors.initials: M
authors.lastname: Choi
authors.forename: Ute I
authors.initials: UI
authors.lastname: Scholl
authors.forename: Peng
authors.initials: P
authors.lastname: Yue
authors.forename: Peyman
authors.initials: P
authors.lastname: Björklund
authors.forename: Bixiao
authors.initials: B
authors.lastname: Zhao
authors.forename: Carol
authors.initials: C
authors.lastname: Nelson-Williams
authors.forename: Weizhen
authors.initials: W
authors.lastname: Ji
authors.forename: Yoonsang
authors.initials: Y
authors.lastname: Cho
authors.forename: Aniruddh
authors.initials: A
authors.lastname: Patel
authors.forename: Clara J
authors.initials: CJ
authors.lastname: Men
authors.forename: Elias
authors.initials: E
authors.lastname: Lolis
authors.forename: Max V
authors.initials: MV
authors.lastname: Wisgerhof
authors.forename: David S
authors.initials: DS
authors.lastname: Geller
authors.forename: Shrikant
authors.initials: S
authors.lastname: Mane
authors.forename: Per
authors.initials: P
authors.lastname: Hellman
authors.forename: Gunnar
authors.initials: G
authors.lastname: Westin
authors.forename: Göran
authors.initials: G
authors.lastname: Åkerström
authors.forename: Wenhui
authors.initials: W
authors.lastname: Wang
authors.forename: Tobias
authors.initials: T
authors.lastname: Carling
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000311:Adrenal Glands / Q000473:pathology; D018246:Adrenocortical Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000450:Aldosterone / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006929:Hyperaldosteronism / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006965:Hyperplasia; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism; D008297:Male; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011188:Potassium / Q000378:metabolism; D055503:Protein Multimerization; D012964:Sodium / Q000378:metabolism; D015384:Zona Glomerulosa / Q000378:metabolism / Q000473:pathology
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C497066:KCNJ3 protein, human; C484274:KCNJ5 protein, human; D050505:Mutant Proteins; D000450:Aldosterone; D012964:Sodium; D011188:Potassium