Characterization of the mechanism by which a nonsense variant in RYR2 leads to disordered calcium handling. Issue 8 (19th April 2022)

• Record Type: Journal Article
• Authors: Hopton, Claire; Tijsen, Anke J.; Maizels, Leonid; Arbel, Gil; Gepstein, Amira; Bates, Nicola; Brown, Benjamin; Huber, Irit; Kimber, Susan J.; Newman, William G.; Venetucci, Luigi; Gepstein, Lior
• Is Part Of: Physiological reports. Volume 10:Issue 8(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-04-19
• Subjects: CPVT -- human induced pluripotent stem cells -- RYR2 -- ventricular arrhythmia; Physiology -- Periodicals; 571
• DOI: 10.14814/phy2.15265
• Languages: English
• ISSNs: 2051-817X

Abstract

Abstract: Heterozygous missense variants of the cardiac ryanodine receptor gene ( RYR2 ) cause catecholaminergic polymorphic ventricular tachycardia (CPVT). These missense variants of RYR2 result in a gain of function of the ryanodine receptors, characterized by increased sensitivity to activation by calcium that results in an increased propensity to develop calcium waves and delayed afterdepolarizations. We have recently detected a nonsense variant in RYR2 in a young patient who suffered an unexplained cardiac arrest. To understand the mechanism by which this variant in RYR2, p.(Arg4790Ter), leads to ventricular arrhythmias, human induced pluripotent stem cells (hiPSCs) harboring the novel nonsense variant in RYR2 were generated and differentiated into cardiomyocytes (RYR2‐hiPSC‐CMs) and molecular and calcium handling properties were studied. 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. 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. Abstract : The RYR2 gene encodes for the cardiac ryanodine receptor, a major calcium handling channel in cardiomyocytes. Heterozygous variants within the RYR2 gene cause the inherited arrhythmia syndrome catecholaminergic polymorphic ventricular tachycardia (CPVT). The majority of these variants are missense changes and lead to a phenotype by a gain of function mechanism. We identified a novel nonsense variant in RYR2 in young women who suffered a cardiac arrest and show, using cardiomyocytes derived from induced pluripotent stem cells, that this variant appears to lead to abnormal calcium handling in a similar mechanism to the previously described gain of function variants.