Characterization of the mechanism by which a nonsense variant in RYR2 leads to disordered calcium handling
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 c...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-04-01
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| Series: | Physiological Reports |
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| Online Access: | https://doi.org/10.14814/phy2.15265 |
| _version_ | 1828402688421789696 |
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| author | Claire Hopton Anke J. Tijsen Leonid Maizels Gil Arbel Amira Gepstein Nicola Bates Benjamin Brown Irit Huber Susan J. Kimber William G. Newman Luigi Venetucci Lior Gepstein |
| author_facet | Claire Hopton Anke J. Tijsen Leonid Maizels Gil Arbel Amira Gepstein Nicola Bates Benjamin Brown Irit Huber Susan J. Kimber William G. Newman Luigi Venetucci Lior Gepstein |
| author_sort | Claire Hopton |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T10:05:05Z |
| format | Article |
| id | doaj.art-0a54c9a572d34f8e990a65b6a055122d |
| institution | Directory Open Access Journal |
| issn | 2051-817X |
| language | English |
| last_indexed | 2024-12-10T10:05:05Z |
| publishDate | 2022-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Physiological Reports |
| spelling | doaj.art-0a54c9a572d34f8e990a65b6a055122d2022-12-22T01:53:16ZengWileyPhysiological Reports2051-817X2022-04-01108n/an/a10.14814/phy2.15265Characterization of the mechanism by which a nonsense variant in RYR2 leads to disordered calcium handlingClaire Hopton0Anke J. Tijsen1Leonid Maizels2Gil Arbel3Amira Gepstein4Nicola Bates5Benjamin Brown6Irit Huber7Susan J. Kimber8William G. Newman9Luigi Venetucci10Lior Gepstein11Division of Evolution and Genomic Sciences Faculty of Biology, Medicine and Health University of Manchester Manchester UKThe Rappaport Faculty of Medicine and Research Institute Technion‐Institute of Technology Haifa IsraelThe Rappaport Faculty of Medicine and Research Institute Technion‐Institute of Technology Haifa IsraelThe Rappaport Faculty of Medicine and Research Institute Technion‐Institute of Technology Haifa IsraelThe Rappaport Faculty of Medicine and Research Institute Technion‐Institute of Technology Haifa IsraelDivision of Cell Matrix Biology and Regenerative Medicine Faculty of Biology, Medicine and Health University of Manchester Manchester UKDepartment of Cardiology Wythenshawe Hospital Manchester University NHS Foundation Trust Manchester UKThe Rappaport Faculty of Medicine and Research Institute Technion‐Institute of Technology Haifa IsraelDivision of Cell Matrix Biology and Regenerative Medicine Faculty of Biology, Medicine and Health University of Manchester Manchester UKDivision of Evolution and Genomic Sciences Faculty of Biology, Medicine and Health University of Manchester Manchester UKDivision of Cardiovascular Sciences Faculty of Biology, Medicine and Health University of Manchester Manchester UKThe Rappaport Faculty of Medicine and Research Institute Technion‐Institute of Technology Haifa IsraelAbstract 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.https://doi.org/10.14814/phy2.15265CPVThuman induced pluripotent stem cellsRYR2ventricular arrhythmia |
| spellingShingle | Claire Hopton Anke J. Tijsen Leonid Maizels Gil Arbel Amira Gepstein Nicola Bates Benjamin Brown Irit Huber Susan J. Kimber William G. Newman Luigi Venetucci Lior Gepstein Characterization of the mechanism by which a nonsense variant in RYR2 leads to disordered calcium handling Physiological Reports CPVT human induced pluripotent stem cells RYR2 ventricular arrhythmia |
| title | Characterization of the mechanism by which a nonsense variant in RYR2 leads to disordered calcium handling |
| title_full | Characterization of the mechanism by which a nonsense variant in RYR2 leads to disordered calcium handling |
| title_fullStr | Characterization of the mechanism by which a nonsense variant in RYR2 leads to disordered calcium handling |
| title_full_unstemmed | Characterization of the mechanism by which a nonsense variant in RYR2 leads to disordered calcium handling |
| title_short | Characterization of the mechanism by which a nonsense variant in RYR2 leads to disordered calcium handling |
| title_sort | characterization of the mechanism by which a nonsense variant in ryr2 leads to disordered calcium handling |
| topic | CPVT human induced pluripotent stem cells RYR2 ventricular arrhythmia |
| url | https://doi.org/10.14814/phy2.15265 |
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