ArticleBioscience reports2021
Identification of loss-of-function RyR2 mutations associated with idiopathic ventricular fibrillation and sudden death.
Article in Bioscience reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 40 citations in OpenAlex.
- Catecholaminergic polymorphic ventricular tachycardia-linked ryanodine receptor variants exhibit domain-specific calcium leak and calmodulin affinity properties.The Journal of physiology · 2026Article
- Characterization of cardiac disease-associated mutations in RyR2 CaAmerican journal of physiology. Cell physiology · 2026Article
- Calcium release channel deficiency syndrome in patients diagnosed with idiopathic ventricular fibrillation and decedents classified as sudden unexplained death in the young.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2026Article
- Prolonged QT Interval in HIV-1 Infected Humanized Mice Treated Chronically with Dolutegravir/Tenofovir Disoproxil Fumarate/Emtricitabine.International journal of molecular sciences · 2026Article
- Identification of Two Rare Variants in Iranian Families With Familial Sudden Cardiac Death.International journal of genomics · 2026Article
- Calcium release deficiency syndrome: an emerging ryanodinopathy.Frontiers in molecular biosciences · 2026Review
- Speckle tracking echocardiography for prediction of arrhythmias in idiopathic ventricular fibrillation.European heart journal. Imaging methods and practice · 2025Article
- Article
- Regional Variation in Cardiovascular Genes Enables a Tractable Genome Editing Strategy.Circulation. Genomic and precision medicine · 2024Article
- Point mutations in RyR2 Ca2+-binding residues of human cardiomyocytes cause cellular remodelling of cardiac excitation contraction-coupling.Cardiovascular research · 2024Article
- Human Genetics of Cardiac Arrhythmias.Advances in experimental medicine and biology · 2024Review
- Calcium Signaling Consequences of RyR2-S4938F Mutation Expressed in Human iPSC-Derived Cardiomyocytes.International journal of molecular sciences · 2023Article
- From gene-discovery to gene-tailored clinical management: 25 years of research in channelopathies and cardiomyopathies.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2023Article
- RYR2-ryanodinopathies: from calcium overload to calcium deficiency.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2023Article
- Role of CaArchives of toxicology · 2023Review
- How does flecainide impact RyR2 channel function?The Journal of general physiology · 2022Article
- Deadly emotional argument: Sudden cardiac death in catecholaminergic polymorphic ventricular tachycardia (CPVT).International journal of cardiology. Heart & vasculature · 2022Article
- Review
- Therapeutic Approaches of Ryanodine Receptor-Associated Heart Diseases.International journal of molecular sciences · 2022Review
- The Genetics and Epigenetics of Ventricular Arrhythmias in Patients Without Structural Heart Disease.Frontiers in cardiovascular medicine · 2022Review
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 5 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mutations in cardiac ryanodine receptor (RyR2) are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT). Most CPVT RyR2 mutations characterized are gain-of-function (GOF), indicating enhanced RyR2 function as a major cause of CPVT. Loss-of-function (LOF) RyR2 mutations have also been identified and are linked to a distinct entity of cardiac arrhythmia termed RyR2 Ca2+ release deficiency syndrome (CRDS). Exercise stress testing (EST) is routinely used to diagnose CPVT, but it is ineffective for CRDS. There is currently no effective diagnostic tool for CRDS in humans. An alternative strategy to assess the risk for CRDS is to directly determine the functional impact of the associated RyR2 mutations. To this end, we have functionally screened 18 RyR2 mutations that are associated with idiopathic ventricular fibrillation (IVF) or sudden death. We found two additional RyR2 LOF mutations E4146K and G4935R. The E4146K mutation markedly suppressed caffeine activation of RyR2 and abolished store overload induced Ca2+ release (SOICR) in human embryonic kidney 293 (HEK293) cells. E4146K also severely reduced cytosolic Ca2+ activation and abolished luminal Ca2+ activation of single RyR2 channels. The G4935R mutation completely abolished caffeine activation of and [3H]ryanodine binding to RyR2. Co-expression studies showed that the G4935R mutation exerted dominant negative impact on the RyR2 wildtype (WT) channel. Interestingly, the RyR2-G4935R mutant carrier had a negative EST, and the E4146K carrier had a family history of sudden death during sleep, which are different from phenotypes of typical CPVT. Thus, our data further support the link between RyR2 LOF and a new entity of cardiac arrhythmias distinct from CPVT.
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