Arrhythmia severity in mouse models harboring RyR2 mutations with varied extent of channel activity

Genetic mutations in the type 2 ryanodine receptor (RyR2) can cause life-threatening arrhythmias, and to date, more than 300 of disease-linked mutations have been reported. Among arrhythmic diseases caused by gain-of-function type RyR2 mutations, catecholaminergic polymorphic ventricular tachycardia (CPVT) is the most common, and its arrhythmia severity ranges from mild to severe depending on mutation sites. In addition, most CPVT-linked RyR mutations are not associated with morphological change in heart, but some RyR2 mutations have reported to cause cardiomyopathy such as dilated cardiomyopathy (DCM) and left ventricular non-compaction (LVNC). The mechanisms underlying the differences in the manifestation of disease phenotypes and the arrhythmia severity are not well understood. We have established a procedure to quantitatively evaluate homozygous mutant RyR2 channel activities using HEK293 cell expression system and investigated the relation to arrhythmia severity in human patients (Kurebayashi at al., J Gen Physiol 2022). Based on the study, we selected multiple lines of mice expressing RyR2 mutations with different degrees of channel activation, and investigated the severity of arrhythmia, the presence or absence of cardiomyopathy, myocardial [3H]ryanodine binding activity, and properties of Ca2+ signals in cardiomyocytes. Our results indicate that arrhythmia severity in RyR2-mutant mice was in good agreement with that predicted from HEK293 cell system.