Complementary somatic mutations of KCNJ5, ATP1A1, and ATP2B3 in sporadic aldosterone producing adrenal adenomas.

Primary aldosteronism (PA) is the most common form of secondary hypertension, accounting for 8–13% among hypertension patients (Mulatero et al. 2013). It is characterized by constitutive production of aldosterone by the adrenal cortex. Among the subtypes of PA, aldosteroneproducing adenomas (APAs), also known as Conn tumors, are characterized by tumors in the adrenal cortex and account for 30–40% of the cases. The two most important physiological stimuli of aldosterone secretion are angiotensin II and serum potassium. Decrease in blood volume activates the renin–angiotensin system, in which angiotensin II signals via the angiotensin receptor. The K concentration across the membrane sets the resting membrane potential. Hyperkalemia causes depolarization of the membrane and generates an action potential to open a voltage-gated Ca channel. In both cases, enhanced intracellular Ca provides the normal signal for aldosterone production. In APAs, autonomous production of aldosterone is found independently of angiotensin II. Recently, next generation sequencing has revealed novel genes frequently mutated in APAs: KCNJ5, ATP1A1, and ATP2B3 (Choi et al. 2011, Taguchi et al. 2012, Beuschlein et al. 2013, Mulatero et al. 2013). In these pivotal studies, mutations in KCNJ5, encoding an inwardly rectifying K channel, were identified in about 30–45% of patients. The K channel encoded by KCNJ5 exists both as homo-tetramer and as a hetero-tetramer with another potassium channel encoded by KCNJ3. The latter has been found more active than homo-tetramers (Choi et al. 2011). More recently, mutations in ATP1A1 (encode a Na/K pump ATPase a subunit) and ATP2B3 (plasma membrane Ca ATPase) have been reported, each of which appears in about 6 and 2% of the tumors respectively (Beuschlein et al. 2013). In this study, we investigated KCNJ5, KCNJ3, ATP1A1, and ATP2B3 for mutations in a series of 35 consecutive patients with