Integrating genetics and genomics in primary aldosteronism
Primary aldosteronism (PA) is the most common form of endocrine hypertension. The two main causes of PA are aldosterone producing adenoma (APA) and bilateral adrenal hyperplasia (BAH). Efficient and timely screening for PA is of major importance, given the severe cardiovascular outcome of aldosterone excess that is independent of blood pressure levels. Yet, the pathogenic mechanisms leading to aldosterone hypersecretion and cell proliferation are largely unknown.
Several studies have addressed the molecular changes underlying APA formation. Transcriptome analyses have highlighted the contribution of different signaling pathways converging upon increased expression of CYP11B2, coding for aldosterone synthase. Less is known with regard to the mechanisms underlying nodulation. Recent evidence indicates a link between APA formation and peritumoral tissue remodelling and ZG hyperplasia, which are major features of adrenals with APA. Both APA and adjacent ZG present characteristics of stem/precursor cells; the re-expression of genes involved in foetal adrenal development could underlie excessive cell proliferation and APA formation.
Recently, a few recurrent somatic mutations of the KCNJ5 gene, coding for the potassium channel Kir3.4, have been implicated as a cause of APA, while inherited mutations of the same gene were identified in familial hyperaldosteronism type 3. Somatic KCNJ5 mutations are found in ~34% of unselected patients with APA; germline KCNJ5 mutations, however, are not similarly causative for BAH. Mutations all lie near or within the selectivity filter of the Kir3.4 channel; they result in a loss of channel selectivity, with increased sodium conductance leading to membrane depolarization. This leads to opening of membrane voltage-dependent calcium channels which is followed by activation of the calcium signaling pathway. While it has been formally established that this cascade of events leads to increased aldosterone production, it remains still unclear whether and how KCNJ5 mutations are responsible for increased cell proliferation.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details are unavailable.