Genetics of mineralocorticoid excess: an update for clinicians.

Aldosterone plays a major role in the regulation of sodium and potassium homeostasis and blood pressure. More recently, aldosterone has emerged as a key hormone mediating end organ damage. In extreme cases, dysregulated aldosterone production leads to primary aldosteronism (PA), the most common form of secondary hypertension. However, even within the physiological range, high levels of aldosterone are associated with an increased risk of developing hypertension over time. PA represents the most common and curable form of hypertension, with a prevalence that increases with the severity of hypertension. Although genetic causes underlying glucocorticoid-remediable aldosteronism, one of the three Mendelian forms of PA, were established some time ago, somatic and inherited mutations in the potassium channel GIRK4 have only recently been implicated in the formation of aldosterone-producing adenoma (APA) and in familial hyperaldosteronism type 3. Moreover, recent findings have shown somatic mutations in two additional genes, involved in maintaining intracellular ionic homeostasis and cell membrane potential, in a subset of APAs. This review summarizes our current knowledge on the genetic determinants that contribute to variations in plasma aldosterone and renin levels in the general population and the genetics of familial and sporadic PA. Various animal models that have significantly improved our understanding of the pathophysiology of excess aldosterone production are also discussed. Finally, we outline the cardiovascular, renal, and metabolic consequences of mineralocorticoid excess beyond blood pressure regulation.

KCNJ5 mutations in aldosterone producing adenoma and relationship with adrenal cortex remodeling.

Somatic mutations of KCNJ5, coding for the potassium channel GIRK4, have recently been implicated in the formation of aldosterone producing adenoma (APA). While a causal link between KCNJ5 mutations, membrane depolarization and aldosterone production has been established, the precise mechanism by which these mutations promote cell proliferation and APA formation remains unclear. The aim of our study was to correlate KCNJ5 mutation status with morphological and functional characteristics of the adrenal cortex adjacent to APA. While GIRK4 was expressed in APA and in the zona glomerulosa of the adjacent cortex, significantly lower levels were detected in APA harboring a KCNJ5 mutation. There was no correlation between KCNJ5 mutation status and the morphological measures of adrenal cortex remodeling, including nodulation, vascularization and expression of CYP11B2. The cell composition of APA was not significantly different between groups. These results indicate that KCNJ5 mutations are not correlated with adrenal cortex remodeling in APA.