Progress in the identification of responsible genes and molecular mechanisms in primary aldosteronism

Abstract

Aldosterone, the mineralocorticoid hormone, plays an important role in blood regulation. Autonomous secretion of aldosterone is known as primary aldosteronism (PA), the most common cause of secondary hypertension. PA comprises a group of heterogenous disorders which makes their classification and management challenging. With the advent of the genomic era several germline and somatic mutations have been identified that are involved in the pathogenesis of primary aldosteronism. This article will review our current knowledge of the genetic mechanisms of familial hyperaldosterism, somatic mutations in genes encoding electrolyte channels and other potential genetic mechanisms implicated in the dysregulation of aldosterone production from in vitro and animal models. There is potential for novel targeted therapies and diagnosis for subsets of patient. The challenges to achieve them are highlighted in this review.

Keywords::

• aldosterone
• genes
• germline
• mutations
• primary aldosteronism
• somatic

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Primary aldosteronism is the cause of 4–10% of cases of hypertension.

• All the cases have inappropriately elevated aldosterone. However, the causes are heterogeneous ranging from an aldosterone-producing adenoma (APA), to idiopathic hyperplasia, unilateral adrenal hyperplasia or autosomal-dominant genetic mutations.

• In Familial Primary Aldosteronism, the genes identified associated with aldosterone excess are a fusion of the cortisol-producing gene CYP11B1 and the APA CYP11B2 in familial hyperaldosteronism (FH)-1; locus 7p22 in FH-II and mutations in a gene encoding a potassium channels (KCNJ5) in FH-III.

• There is potential treatment with specific calcium channel blockers to patients with APA and de novo germline mutations in a calcium channel gene (CACNA1D).

• Somatic mutations in APA resulting in cell depolarization have been attributed to the potassium channel gene KCNJ5, the P-type ATPase pump family genes ATP1A1 and ATP2B3 and the gene of the L-type calcium channel α1 subunit, CACNA1D. The screening for these mutations may aid in the management of subgroups of patients by targeting the altered channel.

• Other mechanisms involved in aldosterone production vary from polymorphisms in the genes related with steroid production (CYP11B1, CYP11B2 and 3βHSD1), cell proliferation and differentiation (TGFβ1), modulation of gene expression (miRNA21 and miRNA24), disruption of other potassium channels (TASK1 and TASK3) and dysregulation of circadian rhythm genes (Cry, Per-1).

• Further investigations for non-APA cases are required.

• The compilation of patients' steroid profiles, with the pathological and genetic characterization of adrenal and blood samples will improve the diagnosis and targeted management of patients with PA.

Notes