Novel Insertion Mutation in KCNJ5 Channel Produces Constitutive Aldosterone Release From H295R Cells

Molecular Endocrinology
Iris HardegeKevin M O'Shaughnessy

Abstract

Primary aldosteronism accounts for 5%-10% of hypertension and in a third of cases is caused by autonomous aldosterone production by adenomas (APA). Somatic mutations in the potassium channel encoded by KCNJ5 have been detected in surgically removed APAs. To better understand the role of these mutations, we resequenced the KCNJ5 channel in a large Australian primary aldosteronism cohort. KCNJ5 mutations were detected in 37 APAs (45% of the cohort), including previously reported E145Q (n = 3), G151R (n = 20), and L168R (n = 13) mutations. In addition, we found a novel 12-bp in-frame insertion mutation (c.414-425dupGCTTTCCTGTTC, A139_F142dup) that duplicates the AFLF sequence in the pore helix upstream of the selectivity filter. Expressed in Xenopus oocytes, the A139_F142dup mutation depolarized the oocytes and produced a G-protein-sensitive Na(+) current with altered K(+) selectivity and loss of inward rectification but retained Ba(2+) sensitivity. Transfected into H295R cells, A139_F142dup increased basal aldosterone release 2.3-fold over the wild type. This was not increased further by incubation with angiotensin II. Although the A139_F142dup mutant trafficked to the plasma membrane of H295R cells, it showed reduced tetramer st...Continue Reading

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Citations

Apr 22, 2016·Journal of Molecular Endocrinology·Namita G HattangadyTobias Else
Dec 10, 2017·Clinical Science·Iris HardegeKevin M O'Shaughnessy
Oct 4, 2017·Endocrine Reviews·Maria-Christina ZennaroFabio Fernandes-Rosa
May 1, 2021·Biomedicines·Kiyotaka ItchoMasayasu Yoneda

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