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Characterisation of the mechanism by which a nonsense variant in RYR2 results in ventricular arrhythmia
- Publication Year :
- 2021
- Publisher :
- Cold Spring Harbor Laboratory, 2021.
-
Abstract
- BackgroundHeterozygous 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.ObjectiveTo understand the mechanism by which a novel nonsense variant in RYR2 p.(Arg4790Ter) leads to ventricular arrhythmias.MethodsHuman 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.ResultsRYR2-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.ConclusionThe 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.
- Subjects :
- medicine.medical_specialty
business.industry
Ryanodine receptor
chemistry.chemical_element
Calcium
Catecholaminergic polymorphic ventricular tachycardia
medicine.disease
Ryanodine receptor 2
Nebivolol
Endocrinology
chemistry
Internal medicine
cardiovascular system
medicine
Missense mutation
business
Carvedilol
Loss function
medicine.drug
Subjects
Details
- Database :
- OpenAIRE
- Accession number :
- edsair.doi...........8e349694e1774e5b4a93e0e741b7c179