Genetics of Primary Aldosteronism

Abstract

Primary aldosteronism is considered the commonest cause of secondary hypertension. In affected individuals, aldosterone is produced in an at least partially autonomous fashion in adrenal lesions (adenomas, [micro]nodules or diffuse hyperplasia). Over the past decade, next-generation sequencing studies have led to the insight that primary aldosteronism is largely a genetic disorder. Sporadic cases are due to somatic mutations, mostly in ion channels and pumps, and rare cases of familial hyperaldosteronism are caused by germline mutations in an overlapping set of genes. More than 90% of aldosterone-producing adenomas carry somatic mutations in K⁺ channel Kir3.4 (KCNJ5), Ca²⁺ channel Ca_V1.3 (CACNA1D), alpha-1 subunit of the Na⁺/K⁺ ATPase (ATP1A1), plasma membrane Ca²⁺ transporting ATPase 3 (ATP2B3), Ca²⁺ channel Ca_V3.2 (CACNA1H), Cl^- channel ClC-2 (CLCN2), β-catenin (CTNNB1), and/or G-protein subunits alpha q/11 (GNAQ/11). Mutations in some of these genes have also been identified in aldosterone-producing (micro)nodules, suggesting a disease continuum from a single cell, acquiring a somatic mutation, via a nodule to adenoma formation, and from a healthy state to subclinical to overt primary aldosteronism. Individual glands can have multiple such lesions, and they can occur on both glands in bilateral disease. Familial hyperaldosteronism, typically with early onset, is caused by germline mutations in steroid 11-beta hydroxylase/ aldosterone synthase (CYP11B1/2), CLCN2, KCNJ5, CACNA1H, and CACNA1D.

Keywords: adenoma; aldosterone; hyperaldosteronism; mutation.

Figure 1.

Somatic and germline mutations in primary aldosteronism (PA). In familial hyperaldosteronism (FH)-I, the CYP11B1/2 hybrid gene (1) is activated by adrenocorticotropic hormone (ACTH) via the MC2R (melanocortin 2 receptor) and cAMP signaling. KCNJ5 mutations (2) in aldosterone-producing adenomas (APAs) and in FH-III lead to abnormal Na⁺ influx, CLCN2 mutations (3) in APAs and in FH-II to higher Cl⁻ efflux, and ATP1A1 (4) and ATP2B3 (5) mutations in APAs to channel like-permeabilities for Na⁺, H⁺, and Ca²⁺, as well as impaired pump function. These effects cause membrane depolarization, activation of voltage-gated calcium channels, calcium influx and increased calcium signaling, stimulating CYP11B2 expression and aldosterone production. Acidification may also play a role in ATP1A1 pathophysiology (not shown). Mutations in CACNA1D (6) and CACNA1H (7) directly increase calcium permeability. GNA11 and GNAQ mutations (8) in APAs prevent termination of G-protein signaling downstream of the AT1R (angiotensin 1 receptor), leading to increased calcium release from intracellular stores. They cooccur with CTNNB1 mutations (9) that prevent β-catenin degradation with increased signaling via the TCF/LEF (T-cell factor/lymphoid enhancer factor) family. Created with BioRender.com. DAG indicates diacyl glycerol; PLC, phospholipase C; IP₃, inositol trisphosphate; and PIP₂, phosphatidylinositol 4,5-bisphosphate.

Figure 2.

Adrenal lesions. Aldosterone-producing micronodules (formerly aldosterone-producing cell clusters [APCCs]) are not recognizable by hematoxylin and eosin staining but stain positive for aldosterone synthase expression. Aldosterone-producing nodules are visible on hematoxylin and eosin staining and are distinguished from aldosterone-producing adenoma (APA) by size. Multiple (micro)nodules can cooccur within a single gland. Aldosterone-producing diffuse hyperplasia shows a broad, uninterrupted strip of aldosterone synthase-positive cells. Nonproducing adenomas stain negative for aldosterone synthase. Brown color indicates aldosterone synthase positivity on immunohistochemistry. Created with BioRendor.com.