A type 2 ryanodine receptor variant associated with reduced Ca2+ release and short-coupled torsades de pointes ventricular arrhythmia

Fujii, Yusuke; Itoh, Hideki; Ohno, Seiko; Murayama, Takashi; Kurebayashi, Nagomi; Aoki, Hisaaki; Blancard, Malorie; Nakagawa, Yoshihisa; Yamamoto, Satoshi; Matsui, Yumie; Ichikawa, Mari; Sonoda, Koji; Ozawa, Tomoya; Ohkubo, Kimie; Watanabe, Ichiro; Guicheney, Pascale; Horie, Minoru

doi:10.1016/j.hrthm.2016.10.015

Cited by 79 publications

(92 citation statements)

References 29 publications

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“…Single-cell Ca 2+ imaging was carried out in HEK293 cells expressing WT or mutant RyR1 and RyR2 15,35 . In Ca 2+ measurements with RyR2, the Ca 2+ signals from cytoplasm ([Ca 2+ ] i ) and ER lumen ([Ca 2+ ] ER ) were monitored using G-GECO1.1 (a gift from Robert Campbell from University of Alberta, Addgene plasmid # 32445) 36 and R-CEPIA1er (a gift from Masamitsu Iino, The University of Tokyo) 37 , respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Microsomes isolated from HEK293 cells expressing WT and mutant RyR2 were incubated for 1 h at 25°C with 5 nM [ 3 H]ryanodine in a medium containing 0.17 M NaCl, 20 mM 3-( N -morpholino)-2-hydroxypropanesulfonic acid (MOPSO) at pH 7.0, 2 mM dithiothreitol, 1 mM AMP, 1 mM MgCl 2 and various concentrations of free Ca 2+ buffered with 10 mM ethylene glycol-bis(2-aminoethylether)-N,N,N’,N’-tetraacetic acid (EGTA) 15,35 . Free Ca 2+ concentrations were calculated using WEBMAXC STANDARD (http://web.stanford.edu/~cpatton/webmaxcS.htm) 38 .…”

Section: Methodsmentioning

confidence: 99%

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A tryptophan residue in the caffeine-binding site of the ryanodine receptor regulates Ca2+ sensitivity

et al. 2018

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Ryanodine receptors (RyRs) are Ca2+ release channels in the sarcoplasmic reticulum of skeletal and cardiac muscles and are essential for muscle contraction. Mutations in genes encoding RyRs cause various muscle and arrhythmogenic heart diseases. Although RyR channels are activated by Ca2+, the actual mechanism of Ca2+ binding remains largely unknown. Here, we report the molecular basis of Ca2+ binding to RyRs for channel activation and discuss its implications in disease states. RyR1 and RyR2 carrying mutations in putative Ca2+ and caffeine-binding sites were functionally analysed. The results were interpreted with respect to recent near-atomic resolution RyR1 structures in various ligand states. We demonstrate that a tryptophan residue in the caffeine-binding site controls the structure of the Ca2+-binding site to regulate the Ca2+ sensitivity. Our results reveal the initial step of RyR channel activation by Ca2+ and explain the molecular mechanism of Ca2+ sensitization by caffeine and disease-causing mutations.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

A tryptophan residue in the caffeine-binding site of the ryanodine receptor regulates Ca2+ sensitivity

et al. 2018

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“…Gain-of-function RyR2 mutations are implicated in catecholaminergic PVT, and 2 loss-of-function missense RyR2 variants associated with scTdP were recently reported. 3,4 The functional consequence of our patient's RyR2 variant, a missense mutation with a change in a single amino acid, is unknown. Although the pathogenicity of this variant remains speculative, it is currently undergoing functional studies.…”

Section: Response To Ecg Challengementioning

confidence: 97%

Idiopathic Ventricular Fibrillation in a 29-Year-Old Man

et al. 2017

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A 29-year-old man with a recent history of cardiac arrest and placement of an implanted cardiac defibrillator (ICD) presented with palpitations and defibrillation shocks. Five months earlier, he had experienced ventricular fibrillation (VF) while seated at his desk job. After resuscitation, an extensive diagnostic evaluation for the etiology of his arrest was undertaken, including left heart catheterization with coronary angiography, a transthoracic echocardiogram, and cardiac magnetic resonance imaging. All of these studies were unremarkable, revealing no evidence of ischemic or structural cardiac disease. He was subsequently discharged after placement of a single-lead endocardial ICD.After discharge, the patient remained asymptomatic until this presentation, when he reported palpitations, light-headedness, and multiple device shocks while awake. These symptoms were coincident with the onset of a febrile, upper respiratory tract infection. Vital signs, physical examination, complete blood count, and electrolyte panel were normal. The patient's 12-lead ECG is shown in Figure 1. What is the most likely diagnosis for this patient, and what is the best course of treatment?Please turn the page to read the diagnosis.

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“…Certain gene mutations in this type of arrhythmia have been recently reported among familial cases . His parents submitted written informed consent for genetic analysis in accordance with the guideline approved by review board in Shiga University of Medical Science.…”

Section: Case Presentationmentioning

confidence: 99%

Electrical storm in an infant with short‐coupled variant of torsade de pointes

Kise

Ohno

Kono

et al. 2018

Journal of Arrhythmia

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A 10‐month‐old infant experienced cardiac arrest caused by ventricular fibrillation (VF). His electrocardiogram (ECG) at rest was within the normal range. Amiodarone was indispensable due to its refractoriness to defibrillation. After implantable cardioverter defibrillator (ICD) implantation, ICD shock was delivered. ICD recordings documented VF and ventricular tachycardia (VT) triggered by premature ventricular contractions with an extremely short coupling interval (240 ms), which were controlled by verapamil. To the best of our knowledge, our case is the first infant with ScTdP. As the electrical storm with ScTdP occurs unpredictably, it can be a cause of sudden infant death syndrome.

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A type 2 ryanodine receptor variant associated with reduced Ca2+ release and short-coupled torsades de pointes ventricular arrhythmia

Abstract: We identified an RyR2 variant associated with reduced Ca release and short-coupled torsades de pointes ventricular arrhythmia. The mechanisms of arrhythmogenesis remain unclear.

Cited by 79 publications

References 29 publications

A tryptophan residue in the caffeine-binding site of the ryanodine receptor regulates Ca2+ sensitivity

A tryptophan residue in the caffeine-binding site of the ryanodine receptor regulates Ca2+ sensitivity

Idiopathic Ventricular Fibrillation in a 29-Year-Old Man

Electrical storm in an infant with short‐coupled variant of torsade de pointes

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