Key result
Patient-derived cardiomyocytes harboring a novel RYR2 nonsense variant displayed significantly more calcium handling abnormalities compared to healthy controls (up to 70.9% vs 28.9%, p<0.001), indicating a gain-of-function mechanism.
Why the study?
Most pathogenic RYR2 variants causing CPVT are gain-of-function missense variants, but some act via loss-of-function mechanisms; the mechanism by which a novel nonsense variant p.(Arg4790Ter) leads to ventricular arrhythmias was unknown.
Absolute Event Rate: 70.9% vs 28.9%
p-value: p=<0.001
The novel RYR2 p.(Arg4790Ter) nonsense variant causes CPVT via a gain-of-function mechanism leading to calcium handling abnormalities, which can be attenuated by carvedilol and nebivolol.
Background Heterozygous variants in the cardiac ryanodine receptor gene ( RYR2 ) cause catecholaminergic polymorphic ventricular tachycardia (CPVT). Most pathogenic RYR2 variants are missense variants which result in a gain of function, causing ryanodine receptors to be increasingly sensitive to activation by calcium, have an increased open probability and an increased propensity to develop calcium waves. However, some RYR2 variants can lead to arrhythmias by a loss of function mechanism. Objective To understand the mechanism by which a novel nonsense variant in RYR2 p.(Arg4790Ter) leads to ventricular arrhythmias. Methods Human induced pluripotent stem cells (hiPSCs) harbouring the novel nonsense variant in RYR2 were differentiated into cardiomyocytes (RYR2-hiPSC-CMs) and molecular and calcium handling properties were studied. Results RYR2-hiPSC-CMs displayed significant calcium handling abnormalities at baseline and following treatment with isoproterenol. Treatment with carvedilol and nebivolol resulted in a significant reduction in calcium handling abnormalities in the RYR2-hiPSC-CMs. Expression of the mutant RYR2 allele was confirmed at the mRNA level and partial silencing of the mutant allele resulted in a reduction in calcium handling abnormalities at baseline. Conclusion The nonsense variant behaves similarly to other gain of function variants in RYR2 . Carvedilol and nebivolol may be suitable treatments for patients with gain of function RYR2 variants.
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Hopton et al. (2021) studied Ventricular arrhythmia / RYR2 nonsense variant (n=1). RYR2 p.(Arg4790Ter) variant vs. Healthy control hiPSC-CMs was evaluated on Percentage of cells displaying calcium handling abnormalities at baseline (p=<0.001). Patient-derived cardiomyocytes harboring a novel RYR2 nonsense variant displayed significantly more calcium handling abnormalities compared to healthy controls (up to 70.9% vs 28.9%, p<0.001), indicating a gain-of-function mechanism.
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