Primary aldosteronism (PA) is the most common and curable form of secondary hypertension. It is caused in the majority of cases by either unilateral aldosterone overproduction due to an aldosterone-producing adenoma (APA) or by bilateral adrenal hyperplasia. Recent advances in genome technology have allowed researchers to unravel part of the genetic abnormalities underlying the development of APA and familial hyperaldosteronism. Recurrent somatic mutations in genes coding for ion channels (KCNJ5 and CACNA1D) and ATPases (ATP1A1 and ATP2B3) regulating intracellular ionic homeostasis and cell membrane potential have been identified in APA. Similar germline mutations of KCNJ5 were identified in a severe familial form of PA, familial hyperaldosteronism type 3 (FH3), whereas de novo germline CACNA1D mutations were found in two cases of hyperaldosteronism associated with a complex neurological disorder. These results have allowed a pathophysiological model of APA development to be established. This model involves modifications in intracellular ionic homeostasis and membrane potential, accounting for ∼50% of all tumors, associated with specific gender differences and severity of PA. In this review, we describe the different genetic abnormalities associated with PA and discuss the mechanisms whereby they lead to increased aldosterone production and cell proliferation. We also address some of the foreseeable consequences that genetic knowledge may contribute to improve diagnosis and patient care.
Keywords: ATPase; aldosterone producing adenoma; bilateral adrenal hyperplasia; calcium channels; endocrine tumor; genetic susceptibility; genotype-phenotype correlation; phenotypic variability; potassium channels; primary aldosteronism; somatic mutations.
© 2015 Society for Endocrinology.