Regulation of SCN5A by Non-coding RNAs in the Brugada Syndrome Context

Abstract

In the human heart, the action potential (AP) is initiated and maintained thanks to a fast-activating fast-inactivating Na + current carried by Nav1.5 channels. The pivotal physiological role of Nav1.5 in the heart is reflected by the important consequences of its coding SCN5A gene mutations. These mutations may lead to an impaired functional expression (including expression level, subcellular localization, trafficking, and/or current density), and are generally correlated with severe cardiac rhythm disorders such as Long QT (LQT) and Brugada syndrome (BrS). In BrS, loss of function mutations in SCN5A account for 35-40% of clinically affected patients and around 400 mutations in the SCN5A gene were identified in probands with BrS. Emerging electrophysiological techniques such as patch clamp along with transgenic animal technologies improved our understanding of the pathogenic mechanisms underlying BrS due to SCN5A variants. However, despite significant advances in defining the pathophysiology of Nav1.5, the molecular mechanisms underlying its regulation and contribution to the disease are poorly understood. It is well established that functional expression of Nav1.5 may be under modulation by post-transcriptional regulators, defining thus its transcript levels in the cell and also the penetrance on its associated diseases. Recently, non-coding RNA (ncRNAs) molecules have been identified as key transcriptional regulators of SCN5A expression in the heart. The present mini-review provides a summary of the role of ncRNAs, especially microRNAs (miRNAs), in the regulation of SCN5A. It mainly focuses on their role in the BrS context and discusses the recent updates and the major gaps still to be elucidated.