3A.04. Characterisation of a novel duplication mutation in KCNJ5 from a patient with an aldosterone producing adenoma

Accounting for 5-10% of hypertension, Primary Aldosteronism (PA) is a condition in which one or both adrenal glands autonomously produce aldosterone, either through bilateral hyperplasia or unilateral aldosterone-producing adenomas (APAs). Recent exome sequencing has revealed that approximately 40% of APAs harbour somatic mutations in the gene KCNJ5, a G-protein regulated inwardly-rectifying potassium channel. In this study, exome sequencing of 87 surgically removed adenomas revealed a novel 12-bp mutation (A139-F142dup). This mutation encodes a duplication of a conserved AFLF motif upstream of the selectivity filter. Clinically, the 54-year-old male patient harbouring the mutant adenoma had severe PA (aldosterone 490 pmol/L, renin 2mU/L, ratio 296). This novel KCNJ5 mutant, when expressed in Xenopus oocytes, exhibited a G-protein-sensitive [Na.sup.+] current, a shift in [K.sup.+]/[Na.sup.+] selectivity and a loss of inward rectification, while retaining [Ba.sup.2+] sensitivity. Expression in the human adrenal carcinoma cell-line H295R led to a 2.3-fold increase in basal aldosterone production, which was not potentiated by addition of angiotensin II, the classical stimulator of aldosterone production. Despite trafficking to the plasma membrane, this novel mutant had reduced tetramer stability and plasma membrane expression. Sanger sequencing of this large cohort of patients supports the major role of somatic KCNJ5 mutations in APAs. Although resulting in similar functional effects to previous mutants, this novel mutation likely acts through an alternative mechanism due to its lack of angiotensin II sensitivity and decreased stability. The discovery of this novel mutation illustrates how the same clinical phenotype can be generated by different mechanisms, even within the same gene. doi: 10.1038/jhh.2015.90