The Role of RyR2 Mutations in Congenital Heart Diseases: Insights Into Cardiac Electrophysiological Mechanisms

Ryanodine receptor 2 (RyR2) protein, a calcium ion release channel in the sarcoplasmic reticulum (SR) of myocardial cells, plays a crucial role in regulating cardiac systolic and diastolic functions. Mutations in RyR2 and its dysfunction are implicated in various congenital heart diseases (CHDs). Studies have shown that mutations in the RYR2 gene, which encodes the RyR2 protein, are linked to several cardiac arrhythmias, including catecholaminergic polymorphic ventricular tachycardia (CPVT), long QT syndrome (LQTS), calcium release deficiency syndrome (CRDS), and atrial fibrillation (AF). Additionally, RyR2 mutations have been associated with multiple genetic cardiomyopathies, such as left ventricular non-compaction cardiomyopathy (LVNC), arrhythmogenic right ventricular cardiomyopathy (ARVC), hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Through various cell and animal models, researchers have developed mutant RyR2 models demonstrated that these mutations often lead to calcium dysregulation, typically resulting in either a gain or loss of function. This comprehensive review delves into the current understanding of RyR2 mutations and their impact on cardiac electrophysiology, focusing on the molecular mechanisms linking these mutations to arrhythmias and cardiomyopathies-an essential step in advancing diagnostic and therapeutic strategies.