Genetic and Genomic Mechanisms of Primary Aldosteronism

• Published in: Trends in molecular medicine Vol. 26; no. 9; pp. 819 - 832
• Main Authors: Fernandes-Rosa, Fabio L., Boulkroun, Sheerazed, Zennaro, Maria-Christina
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.09.2020; Elsevier
• Subjects: Cardiology and cardiovascular system; Endocrinology and metabolism; Genetics; Human genetics; Human health and pathology; Life Sciences
• ISSN: 1471-4914; 1471-499X; 1471-499X
• DOI: 10.1016/j.molmed.2020.05.005

Aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia are the main cause of primary aldosteronism (PA), the most frequent form of secondary hypertension. Mutations in ion channels and ATPases have been identified in APA and inherited forms of PA, highlighting the central role of calcium signaling in PA development. Different somatic mutations are also found in aldosterone-producing cell clusters in adrenal glands from healthy individuals and from patients with unilateral and bilateral PA, suggesting additional pathogenic mechanisms. Recent mouse models have also contributed to a better understanding of PA. Application of genetic screening in familial PA, development of surrogate biomarkers for somatic mutations in APA, and use of targeted treatment directed at mutated proteins may allow improved management of patients. The identification of mutations in genes coding for ion channels and ATPases responsible for sporadic and inherited forms of primary aldosteronism (PA) represents a major advance in our knowledge of PA.The use of CYP11B2 immunohistochemistry-guided next generation sequencing allowed the identification of somatic mutations in aldosterone producing adenomas (APA)-driver genes in >90% of APA.The identification of germline mutations in genes coding for ion channels has allowed the establishment of a new classification of familial forms of PA into familial hyperaldosteronism (FH)-I to FH-IV, based on the underlying genetic defect.The description of different mutational events in aldosterone producing cell clusters (APCCs) and micronodules within the same adrenal gland with APA opens new perspectives for the understanding of the pathogenic mechanisms leading to APA development.