Molecular characterization of the calcium release channel deficiency syndrome

Tester, David J.; Kim, C S John; Hamrick, Samantha K; Ye, Dan; O’Hare, Bailey J.; Bombei, Hannah; Fitzgerald, K.; Haglund-Turnquist, Carla; Atkins, Dianne L.; Núñez, Lisardo; Law, Ian H.; Temple, Joel; Ackerman, Michael J.

doi:10.1172/jci.insight.135952

Cited by 19 publications

(10 citation statements)

References 26 publications

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“…In addition, RyR2 mutations have also been implicated in non-stress-induced cardiac disease including long QT syndrome [ 57 , 58 ], torsade de pointes [ 59 , 60 ], left ventricular noncompaction [ 61 , 62 ], dilated cardiomyopathy [ 63 , 64 ], and hypertrophic cardiomyopathy [ 65 ]. Very recently, a new disease termed RyR2 Ca 2+ release deficiency syndrome (CRDS) was described, underlined by RyR2 loss of function (LoF) mutations [ 66 , 67 ]. CRDS is characterized by ventricular arrhythmias and sudden cardiac death but a negative exercise stress testing for CPVT.…”

Section: Cardiac Disease Associated With Ryr2 Mutationsmentioning

confidence: 99%

“…In terms of disease diagnosis, there is no apparent correlation between the location of mutations on the RyR2 structure and the clinical phenotype presenting as typical or atypical CPVT. On the other hand, the few deletions, insertions, and nonsense mutations reported to date are often associated with atypical CPVT or cardiomyopathy irrespective of their location on the RyR2 structure (e.g., [ 61 , 63 , 67 , 69 ]).…”

Section: Molecular Mechanisms Of Genetic Ryr2 Diseasementioning

confidence: 99%

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Molecular, Subcellular, and Arrhythmogenic Mechanisms in Genetic RyR2 Disease

Fowler

Zissimopoulos

2022

Biomolecules

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The ryanodine receptor (RyR2) has a critical role in controlling Ca2+ release from the sarcoplasmic reticulum (SR) throughout the cardiac cycle. RyR2 protein has multiple functional domains with specific roles, and four of these RyR2 protomers are required to form the quaternary structure that comprises the functional channel. Numerous mutations in the gene encoding RyR2 protein have been identified and many are linked to a wide spectrum of arrhythmic heart disease. Gain of function mutations (GoF) result in a hyperactive channel that causes excessive spontaneous SR Ca2+ release. This is the predominant cause of the inherited syndrome catecholaminergic polymorphic ventricular tachycardia (CPVT). Recently, rare hypoactive loss of function (LoF) mutations have been identified that produce atypical effects on cardiac Ca2+ handling that has been termed calcium release deficiency syndrome (CRDS). Aberrant Ca2+ release resulting from both GoF and LoF mutations can result in arrhythmias through the Na+/Ca2+ exchange mechanism. This mini-review discusses recent findings regarding the role of RyR2 domains and endogenous regulators that influence RyR2 gating normally and with GoF/LoF mutations. The arrhythmogenic consequences of GoF/LoF mutations will then be discussed at the macromolecular and cellular level.

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Section: Cardiac Disease Associated With Ryr2 Mutationsmentioning

confidence: 99%

Section: Molecular Mechanisms Of Genetic Ryr2 Diseasementioning

confidence: 99%

Molecular, Subcellular, and Arrhythmogenic Mechanisms in Genetic RyR2 Disease

Fowler

Zissimopoulos

2022

Biomolecules

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“…It is logical to infer that flecainide might exacerbate the CRDS phenotype if it can inhibit RyR2. To date, flecainide has proven to be a promising therapeutic agent for CRDS ( Tester et al, 2020 ; Ormerod et al, 2021 ). The programmed electrical stimulation protocol with a pattern of long-burst, long-pause, and short-coupled (LBLPS) can induce ventricular arrhythmias in transgenic mice with RyR2 LOF mutations.…”

Section: Flecainide Treatment In Calcium-release Deficiency Syndromementioning

confidence: 99%

“… Sun et al (2021) demonstrated that treatment with flecainide abolished LBLPS-induced ventricular arrhythmias in model mice. In the induced pluripotent stem cell cardiomyocytes carrying homozygous RYR2 duplication, which presented LOF, Tester et al (2020) reported that flecainide significantly reduced arrhythmic activity caused by isopropanol. Ormerod et al (2021) tested flecainide in nine CRDS patients and found that the administration of flecainide substantially reduced arrhythmia inducibility in one subject and abolished arrhythmia in all others.…”

Section: Flecainide Treatment In Calcium-release Deficiency Syndromementioning

confidence: 99%

The Antiarrhythmic Mechanisms of Flecainide in Catecholaminergic Polymorphic Ventricular Tachycardia

Peng

Lin

et al. 2022

Front. Physiol.

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Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe yet rare inherited arrhythmia disorder. The cornerstone of CPVT medical therapy is the use of β-blockers; 30% of patients with CPVT do not respond well to optimal β-blocker treatment. Studies have shown that flecainide effectively prevents life-threatening arrhythmias in CPVT. Flecainide is a class IC antiarrhythmic drug blocking cardiac sodium channels. RyR2 inhibition is proposed as the principal mechanism of antiarrhythmic action of flecainide in CPVT, while it is highly debated. In this article, we review the current progress of this issue.

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“…During cardiac excitation–contraction coupling, a minor amount of extracellular Ca 2+ enters the cytoplasm through L-type voltage gated calcium channels, triggering the release of large amounts of Ca 2+ into the cytoplasm through RyR2 channels and causing cardiomyocyte contraction. Upon completion of the cardiomyocyte contraction, most of the cytoplasmic Ca 2+ is reabsorbed into ER via SERCA2 ( Tester et al, 2020 ). Apart from the RyR2 protein level, the function of RyR2 is also regulated by its phosphorylation at Ser 2,808 ( Baine et al, 2020 ; Potenza et al, 2020 ).…”

Section: Biological Functions Of Mercsmentioning

confidence: 99%

Mitochondria-endoplasmic reticulum contacts in sepsis-induced myocardial dysfunction

Jiang

Wang

et al. 2022

Front. Cell Dev. Biol.

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Mitochondrial and endoplasmic reticulum (ER) are important intracellular organelles. The sites that mitochondrial and ER are closely related in structure and function are called Mitochondria-ER contacts (MERCs). MERCs are involved in a variety of biological processes, including calcium signaling, lipid synthesis and transport, autophagy, mitochondrial dynamics, ER stress, and inflammation. Sepsis-induced myocardial dysfunction (SIMD) is a vital organ damage caused by sepsis, which is closely associated with mitochondrial and ER dysfunction. Growing evidence strongly supports the role of MERCs in the pathogenesis of SIMD. In this review, we summarize the biological functions of MERCs and the roles of MERCs proteins in SIMD.

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Molecular characterization of the calcium release channel deficiency syndrome

Abstract: are involved in an equity/royalty relationship (no patent numbers involved) with AliveCor, Blue Ox Healthcare Partners, and StemoniX.

Cited by 19 publications

References 26 publications

Molecular, Subcellular, and Arrhythmogenic Mechanisms in Genetic RyR2 Disease

Molecular, Subcellular, and Arrhythmogenic Mechanisms in Genetic RyR2 Disease

The Antiarrhythmic Mechanisms of Flecainide in Catecholaminergic Polymorphic Ventricular Tachycardia

Mitochondria-endoplasmic reticulum contacts in sepsis-induced myocardial dysfunction

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