Identifying potential functional impact of mutations and polymorphisms: linking heart failure, increased risk of arrhythmias and sudden cardiac death

Abstract

Researchers and clinicians have discovered several important concepts regarding the mechanisms responsible for increased risk of arrhythmias, heart failure, and sudden cardiac death. One major step in defining the molecular basis of normal and abnormal cardiac electrical behavior has been the identification of single mutations that greatly increase the risk for arrhythmias and sudden cardiac death by changing channel-gating characteristics. Indeed, mutations in several genes encoding ion channels, such as SCN5A, which encodes the major cardiac Na+ channel, have emerged as the basis for a variety of inherited cardiac arrhythmias such as long QT syndrome, Brugada syndrome, progressive cardiac conduction disorder, sinus node dysfunction, or sudden infant death syndrome. In addition, genes encoding ion channel accessory proteins, like anchoring or chaperone proteins, which modify the expression, the regulation of endocytosis, and the degradation of ion channel a-subunits have also been reported as susceptibility genes for arrhythmic syndromes. The regulation of ion channel protein expression also depends on a fine-tuned balance among different other mechanisms, such as gene transcription, RNA processing, post-transcriptional control of gene expression by miRNA, protein synthesis, assembly and post-translational modification and trafficking. The aim of this review is to inventory, through the description of few representative examples, the role of these different biogenic mechanisms in arrhythmogenesis, HF and SCD in order to help the researcher to identify all the processes that could lead to arrhythmias. Identification of novel targets for drug intervention should result from further understanding of these fundamental mechanisms.

Brugada Syndrome: Oligogenic or Mendelian Disease?

“…In one study investigating the consequences of K V 4.3 overexpression on Na V 1.5 current and consequent sodium channel availability, the authors concluded that the current of the Na V 1.5 protein was directly impacted by several factors, including the gain-of-function of the K V 4.3 protein encoded for by the KCND3 gene [62]. It has been suggested that post-translational modifications, such as a defect in the splicing process [93] or trafficking [94,95], or a modification in phosphorylation, methylation, or acetylation [96], could explain alterations in the function of the channel encoded by SCN5A in the absence of mutations in this gene itself. Also, the predicted phenotypic effect of a particular variant should take into consideration that ancestry can affect the pathogenicity of a particular variant [97].…”

Current and Potential Antiarrhythmic Drugs Targeting Voltage-Gated Cardiac Ion Channels

“…A number of mutations on SCN5A gene lead to dysregulation of Na v 1.5 trafficking to the surface membrane resulting in reduced Na + current amplitude [47]. In this case, use of Na v 1.5 activators appears to be a promising prospective as they could compensate for the loss of Na + permeability and possibly restore cardiac function.…”

Personalized Medicine Applied to Forensic Sciences: New Advances and Perspectives for a Tailored Forensic Approach

“…Variants of LQTS may contribute to susceptibility for diTdP in a percentage on average around 5-10% of subjects. Identification of these cases emphasizes the emerging role of preventive medicine [47][48][49][50][51][52][53][54][55][56][57][58].…”