Mutations in KCNJ5 gene cause hyperaldosteronism.

A new report in Science finds that a few somatic KCNJ5 mutations explain a subset of aldosteroneproducing adenomas, the most frequent secondary cause of arterial hypertension. Primary aldosteronism (PAL) is the most common secondary form of arterial hypertension, with an estimated prevalence between 6% and 10% and as high as 20% in patients with resistant hypertension. In the majority of cases, it is the result of either an adrenal aldosterone producing adenoma (APA) or a bilateral adrenal hyperplasia (also known as idiopathic hyperaldosteronism). However, the molecular mechanisms underlying aldosterone hypersecretion and nodulation of the adrenal cortex are still largely unknown. In this article, Lifton’s group opens a completely new area by establishing the concept that recurrent somatic mutations at the KCNJ5 gene coding for the potassium channel Kir3.4 could account for a substantial proportion of APAs but also that a germinal KCNJ5 mutation can cause a very rare autosomal dominant and early-onset form of PAL, characterized by bilateral massive adrenal hyperplasia and referred to as FH-3. Using whole exome sequencing on four APA blood DNA pairs from unrelated subjects, the authors have identified somatic mutations of the KCNJ5 gene in two tumors; sequencing of another 18 APA identified six additional cases with KCNJ5 mutations. Remarkably, only two recurrent mutations were found, G151R and L168R, affecting two residues in and near the selectivity filter of the Kir3.4 potassium channel. A similar heterozygous-inherited germinal mutation, T158A, located in the same conserved region, was also found in the previously described FH-3 kindred. KCNJ5 encodes the inwardly rectifying K channel Kir3.4 that exists both as homotetramers and heterotetramers with Kir3.1. Using electrophysiologic studies, the authors clearly demonstrated that these mutations result in loss of channel selectivity, with increased sodium conductance leading to membrane depolarization. Importantly, in zona glomerulosa cells, the site of aldosterone production in the adrenal cortex, membrane depolarization leads to opening of voltage-activated Ca channels, with activation of the calcium signaling pathway, the major mediator of aldosterone production. From their results, the authors conclude that KCNJ5 mutations are involved in inherited and acquired aldosteronism with cell autonomous proliferation and that they are sufficient for both constitutive aldosterone secretion and cell proliferation. These results are of utmost importance because they open the possibility that a hormonal adrenal disease affecting millions of individuals worldwide could, in part, be caused by one single mechanism, ie, somatic adrenal mutations affecting a potassium channel. As such, this revolution in the endocrine and cardiovascular fields raises some questions. One surprising finding is that similar KCNJ5 mutations lead either to APA formation, in the case of somatic mutations, or to massive bilateral adrenal hyperplasia without nodulation when inherited. Indeed, the three affected family members carrying a germ line T158A KCNJ5 mutation all underwent bilateral adrenalectomy, which showed diffuse hyperplasia of the zona fasciculata and no evidence of nodularity. These results are in contradiction with what would be expected from a gene predominantly expressed in the zona glomerulosa but are in line with observations in transgenic animals inactivated for TASK1 and TASK3 channels, the major contributors to the maintenance of background potassium conductance. TASK1 knock-out mice present a complex phenotype of severe sex-dependent hyperaldosteronism resulting from abnormal expression of aldosterone synthase in the adrenal zona fasciculata, whereas removal of an important background K current in TASK1/TASK3 double knock-out animals leads to autonomous aldosterone production. Remarkably, this phenotype is not accompanied by any alteration of adrenal gland morphology and zonation. These results may imply that in addition to increased Ca signaling, activation of other, as yet unknown, pathways is required to promote zona glomerulosa autonomous cell proliferation and nodulation in APA. They also suggest that more subtle germinal mutations of the KNCJ5 gene may be responsible for bilateral adrenal hyperplasia, the other main cause of PAL. Another surprise is the absence of extraadrenal manifestations in the previously described FH3 family because Kir3.4 as well as its dimerization partner Kir3.1 are highly expressed in other tissues, especially the heart. Recently, KCNJ5 missense mutations have been identified in a patient with atrial fibrillation and in a family with autosomal dominant long QT syndrome, a hereditary disorder that leads to sudden The opinions expressed in this Commentary are not necessarily those of the editors or of the American Heart Association. Commentaries serve as a forum in which experts highlight and discuss articles (published elsewhere) that the editors of Circulation Research feel are of particular significance to cardiovascular medicine. Commentaries are edited by Aruni Bhatnagar and Ali J. Marian. From the INSERM, UMRS_970, Paris Cardiovascular Research Center; the University Paris Descartes; and Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France. Correspondence to Maria-Christina Zennaro, MD, PhD or Xavier Jeunemaitre, MD, PhD, INSERM U970—PARCC, 56 rue Leblanc, 75015 Paris, France. E-mail [email protected]; or [email protected] (Circ Res. 2011;108:1417-1418.) © 2011 American Heart Association, Inc.