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 ), Ca 2+ channel Ca V 1.3 ( CACNA1D ), alpha-1 subunit of the Na + /K + ATPase ( ATP1A1 ), plasma membrane Ca 2+ transporting ATPase 3 ( ATP2B3 ), Ca 2+ channel Ca V 3.2 ( CACNA1H ), Cl − channel ClC-2 ( CLCN2 ), β-catenin ( CTNNB1 ), and 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 .

Primary aldosteronism: Pathophysiological mechanisms of cell death and proliferation

“…Solitary GNA11 mutations were also identified in the hyperplastic zona glomerulosa layer of the adrenal cortex adjacent to APAs with GNA11 and CTNNB1 mutations ( 18 ). This supports the 2-hit model of tumorigenesis in APA development ( 56 ) in which a first event stimulates adrenocortical cell proliferation, and a second event (a somatic aldosterone-driver mutation) drives autonomous aldosterone production ( 4 , 57 , 58 ).…”

“…An extensive review on the genetics of PA has been published recently ( 4 ). In brief, FH type 1 is caused by a chimeric CYP11B1 / CYP11B2 gene composed of the adrenocorticotropic hormone (ACTH)-responsive promoter region of CYP11B1 fused to the CYP11B2 coding region ( 5 ).…”

“…The resultant depolarization of zona glomerulosa cells causes opening of voltage-gated calcium channels, increased intracellular calcium concentrations and activation of calcium signal transduction and CYP11B2 (aldosterone synthase) gene transcription and increased aldosterone production ( 6 ) ( Figure 1 ). KCNJ5 mutations are highly prevalent in APAs ( 3 , 4 ), associated with larger adenoma size, female sex, and more severe aldosteronism ( 28 ). The application of genotype analysis to CYP11B2 (aldosterone synthase) immunopositive regions of paraffin-embedded adrenal sections combined with next generation sequencing ( 29 ) has resulted in an increased detection of somatic APA mutations such that prevalence rates are now described in around 90% of cases ( 22 – 25 , 27 , 30 ).…”

“…Bilateral forms include familial forms of PA, which are rare monogenic forms of hypertension caused by germline pathogenic variants. To date, 4 genetically distinct forms of familial hyperaldosteronism have been identified (FH types 1 to 4), classified according to the affected gene ( 3 , 4 ). Sporadic aldosterone-producing adenomas (APAs) carry somatic mutations in aldosterone-driver genes and in genes that drive the development of multiple adrenal tumors.…”

TSPAN12 (Tetraspanin 12) Is a Novel Negative Regulator of Aldosterone Production in Adrenal Physiology and Aldosterone-Producing Adenomas

“…2 Somatic APA mutations in some ion pumps and channels can cause a disturbance in intracellular ion homeostasis resulting in activation of Ca 2+ signaling, which drives an increase in CYP11B2 (aldosterone synthase) gene expression and aldosterone production. 3 CYP11B2 immunohistochemistry-guided next generation sequencing has helped identify somatic aldosterone-driver mutations in more than 90% APAs. 4,5…”