دورية أكاديمية
أعرض في EDS

Characterization of the mechanism by which a nonsense variant in RYR2 leads to disordered calcium handling.

التفاصيل البيبلوغرافية
العنوان: Characterization of the mechanism by which a nonsense variant in RYR2 leads to disordered calcium handling.
المؤلفون: Hopton C; Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.; Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.; Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK., Tijsen AJ; The Rappaport Faculty of Medicine and Research Institute, Technion-Institute of Technology, Haifa, Israel.; Amsterdam UMC, Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam, The Netherlands., Maizels L; The Rappaport Faculty of Medicine and Research Institute, Technion-Institute of Technology, Haifa, Israel.; Division of Cardiology, Sheba Medical Center Hospital, Tel Hashomer, Israel.; The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.; The Talpiot Sheba Medical Leadership Program, Israel., Arbel G; The Rappaport Faculty of Medicine and Research Institute, Technion-Institute of Technology, Haifa, Israel., Gepstein A; The Rappaport Faculty of Medicine and Research Institute, Technion-Institute of Technology, Haifa, Israel., Bates N; Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK., Brown B; Department of Cardiology, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK., Huber I; The Rappaport Faculty of Medicine and Research Institute, Technion-Institute of Technology, Haifa, Israel., Kimber SJ; Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK., Newman WG; Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.; Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK., Venetucci L; Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.; Manchester Heart Centre, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK., Gepstein L; The Rappaport Faculty of Medicine and Research Institute, Technion-Institute of Technology, Haifa, Israel.; Cardiology Department, Rambam Health Care Campus, Haifa, Israel.
المصدر: Physiological reports [Physiol Rep] 2022 Apr; Vol. 10 (8), pp. e15265.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society Country of Publication: United States NLM ID: 101607800 Publication Model: Print Cited Medium: Internet ISSN: 2051-817X (Electronic) Linking ISSN: 2051817X NLM ISO Abbreviation: Physiol Rep Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [Malden MA] : published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society, 2013-
مواضيع طبية MeSH: Induced Pluripotent Stem Cells*/metabolism , Ryanodine Receptor Calcium Release Channel*/genetics , Ryanodine Receptor Calcium Release Channel*/metabolism, Calcium/metabolism ; Calcium Signaling ; Carvedilol ; Humans ; Mutation ; Myocytes, Cardiac/metabolism ; Nebivolol/metabolism
مستخلص: 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.
(© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)
التعليقات: Erratum in: Physiol Rep. 2022 Aug;10(15):e15428. (PMID: 35938525)
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معلومات مُعتمدة: MR/S002553/1 United Kingdom MRC_ Medical Research Council; IS-BRC-1215-20007 Manchester NIHR BRC; FS/16/33/32196 United Kingdom BHF_ British Heart Foundation; United Kingdom DH_ Department of Health
فهرسة مساهمة: Keywords: CPVT; RYR2; human induced pluripotent stem cells; ventricular arrhythmia
المشرفين على المادة: 0 (RyR2 protein, human)
0 (Ryanodine Receptor Calcium Release Channel)
030Y90569U (Nebivolol)
0K47UL67F2 (Carvedilol)
SY7Q814VUP (Calcium)
تواريخ الأحداث: Date Created: 20220419 Date Completed: 20220421 Latest Revision: 20230315
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC9017975
DOI: 10.14814/phy2.15265
PMID: 35439358
قاعدة البيانات: MEDLINE
الوصف
تدمد:2051-817X
DOI:10.14814/phy2.15265