Prevalence, Clinical, and Molecular Correlates of KCNJ5 Mutations in Primary Aldosteronism

Abstract

Abstract-Primary aldosteronism is the most common form of secondary hypertension. Mutations in the KCNJ5 gene have been described recently in aldosterone-producing adenomas (APAs). The aim of this study was to investigate the prevalence of KCNJ5 mutations in unselected patients with primary aldosteronism and their clinical, biological and molecular correlates. KCNJ5 sequencing was performed on somatic (APA, nϭ380) and peripheral (APA, nϭ344; bilateral adrenal hyperplasia, nϭ174) DNA of patients with primary aldosteronism, collected through the European Network for the Study of Adrenal Tumors. Transcriptome analysis was performed in 102 tumors. Somatic KCNJ5 mutations (p.Gly151Arg or p.Leu168Arg) were found in 34% (129 of 380) of APA. They were significantly more prevalent in females (49%) than males (19%; PϽ10 Ϫ3) and in younger patients (42.1Ϯ1.0 versus 47.6Ϯ0.7 years; PϽ10 Ϫ3 ) and were associated with higher preoperative aldosterone levels (455Ϯ26 versus 376Ϯ17 ng/L; Pϭ0.012) but not with therapeutic outcome after surgery. Germline KCNJ5 mutations were found neither in patients with APA nor those with bilateral adrenal hyperplasia. Somatic KCNJ5 mutations were specific for APA, because they were not identified in 25 peritumoral adrenal tissues or 16 cortisol-producing adenomas. Hierarchical clustering of transcriptome profiles showed that APAs with p.Gly151Arg or p.Leu168Arg mutations were indistinguishable from tumors without KCNJ5 mutations. In conclusion, although a large proportion of sporadic APAs harbors somatic KCNJ5 mutations, germline mutations are not similarly causative for bilateral adrenal hyperplasia. KCNJ5 mutation carriers are more likely to be females; younger age and higher aldosterone levels at diagnosis suggest that KCNJ5 mutations may be associated with a more florid phenotype of primary aldosteronism. H ypertension is a major cardiovascular risk factor that affects between 10% and 40% of the population in industrialized countries. Detection of secondary forms of hypertension is particularly important because it allows for the targeted management of the underlying disease. Primary aldosteronism (PA) is the most common form of secondary hypertension, with an estimated prevalence between 6% and 12% of hypertensives and as high as 20% in patients with resistant hypertension. 1-5 PA occurs as the result of a dysregulation of the mechanisms controlling adrenal aldosterone production, ultimately leading to hypertension with low plasma renin and elevated aldosterone sometimes associated with hypokalemia. Among subtypes of PA, aldosteroneproducing adenoma (APA) and bilateral adrenal hyperplasia (BAH; also known as idiopathic hyperaldosteronism) together account for Ϸ95% of cases. [1][2][3] Aldosterone production from the adrenal zona glomerulosa is tightly controlled to maintain electrolyte and fluid homeostasis by the kidney. Thus, the two most important physiological stimuli of aldosterone secretion are angiotensin II and serum potassium. Glomerulosa cell membrane depolarization leads to openi...

Visinin-Like 1 Is Upregulated in Aldosterone-Producing Adenomas With KCNJ5 Mutations and Protects From Calcium-Induced Apoptosis

“…8,9 The frequency of these somatic mutations in a large multicenter European study was determined as 34% (range: 14% to 50%, with the diversity probably related to differences in diagnostic strategies and patient selection for adrenalectomy). 16 The APA samples used in the present study correspond with a subset used for this analysis. 16 These are composed of 31 APAs, of which 14 carry KCNJ5 mutations with the G151R mutation predominating, accounting for 10 of the KCNJ5 mutations.…”

“…16 The APA samples used in the present study correspond with a subset used for this analysis. 16 These are composed of 31 APAs, of which 14 carry KCNJ5 mutations with the G151R mutation predominating, accounting for 10 of the KCNJ5 mutations.…”

“…DNA sequencing was performed as described in Boulkroun et al 16 The APA samples used in the present study correspond with those of the Torino group used in the study of Boulkroun et al 16 in which 45% carry KCNJ5 mutations and were G151R (nϭ10), L168R (nϭ3), and T158A (nϭ1). All of the mutations described in this study are somatic mutations: the T158A mutation was first described by Choi A, VSNL1 cDNA fragment was amplified by semiquantitative RT-PCR using first-strand cDNA templates reverse transcribed from total RNA isolated from H295R cells (H295) or from pooled cDNAs produced from APA transcripts (APA) or from normal adrenals (NA), as described 10 (A).…”

Progrès récents dans la génétique de l’hyperaldostéronisme primaire

“…Ainsi, deux études multicentriques consécutives réalisées au sein du réseau européen d'étude des tumeurs de la surrénales 4 ont éva-lué l'éventail génétique et les corrélations cliniques des mutations somatiques chez les patients porteurs d'adénomes produisant de l'aldostérone [14,15]. L'analyse de 474 patients issus de sept centres différents a identifié des mutations somatiques chez 54 % des patients porteurs d'adénomes ; cette prévalence varie de 27,2 % à 56,8 % selon les centres.…”

“…Les mutations KCNJ5 sont les anomalies génétiques les plus fréquentes (prévalence de 38 %) ; les mutations ATP1A1 et ATP2B3 sont présentes respectivement dans 5,3 % et 1,7 % des adénomes produisant de l'aldostérone. La fréquence de ces mutations concorde avec celle rapportée à partir d'autres cohortes [9,11,16], bien que les mutations KCNJ5 soient plus ou moins fréquentes dans certaines populations et selon les procédures diagnostiques utilisées [14,17,18]. Les mutations du gène CACNA1D sont les secondes mutations les plus fréquentes après les mutations KCNJ5 et leur prévalence est de 9,3 % [15].…”