A novel cardiac ryanodine receptor gene (RyR2) mutation in an athlete with aborted sudden cardiac death: a case of adult-onset catecholaminergic polymorphic ventricular tachycardia

Arakawa, Junko; Hamabe, Akira; Aiba, Takeshi; Nagai, Tomoo; Yoshida, Mikoto; Touya, Takumi; Ishigami, Norio; Hisadome, Hideki; Katsushika, Shuichi; Tabata, Hidenori; Miyamoto, Yoshihiro; Shimizu, Wataru

doi:10.1007/s00380-014-0555-y

Cited by 13 publications

(8 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Notably, a patient with K4392R did not show any difference from WT. The mother of this patient bears the same mutation and is asymptomatic (Arakawa et al, 2015). After the publication of this report, K4392R (rs753733164) was found to be a benign variant that does not exert arrhythmogenic effects in a majority of its carriers.…”

Section: Pathological Relevance Of Cicr Activity In Cpvt Mutationsmentioning

confidence: 82%

“…Furthermore, other genetic and environmental factors are also considered to be involved in human diseases. (Nishio et al, 2008) R2474S 8y M (syncope)* 7y M (SUD)* helical domain, helix 7a (Priori et al, 2001) (Priori et al, 2002) D3638A (not conserved) (Arakawa et al, 2015) R4497C 30y F (palpitation) 14y F, 16y F (SCD) 28y, 36y (biVT on exercise test), 59y F (asymptomatic) S1' (Priori et al, 2001) (Tester et al, 2004) K4751Q 6y F (CPVT and AF) Joint region between S4 and S4-S5 linker (Kawamura et al, 2013;Uehara et al, 2017) H4762P 13y F (VT)** Her mother and 2 children are clinically unaffected S4-S5 linker (Postma et al, 2005) K4805R 2y F pore forming loop (Medeiros-Domingo et al, 2009) (Lieve et al, 2019) I4867M 9y M S6 (Priori et al, 2002) *Twin brothers.…”

Section: Limitationsmentioning

confidence: 99%

See 1 more Smart Citation

Enhanced CICR activity reduces ER Ca²⁺level in cells expressing CPVT-linked mutant RyR2

Kurebayashi

Murayama

Ohta

et al. 2021

Preprint

View full text Add to dashboard Cite

Type 2 ryanodine receptor (RyR2) is a cardiac Ca2+ release channel in the endoplasmic reticulum (ER). Mutations in RyR2 are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT), which is considered to be associated with enhanced spontaneous Ca2+ release. This spontaneous Ca2+ release tends to occur when ER Ca2+ ([Ca2+]ER) reaches a certain threshold level, and CPVT mutations are reported to lower this threshold. There are two explanations for this lowered threshold: the mutations increase sensitivity to luminal Ca2+ or they enhance cytosolic [Ca2+] ([Ca2+]cyt)-induced Ca2+ release (CICR) activity. However, no quantitative analysis of this issue has been performed so far. Here, we quantitatively explored how the change in CICR activity of RyR2 affects the threshold [Ca2+]ER experimentally and by model-based simulation. Wild-type (WT) and CPVT-linked mutant RyR2s were expressed in HEK293 cells. [Ca2+]cyt and [Ca2+]ER measurements with Ca2+ indicators revealed that CPVT RyR2 cells showed higher oscillation frequency and lower threshold [Ca2+]ER in a mutation-specific manner compared with WT cells. The CICR activity of mutant RyR2s was assessed by Ca2+-dependent [3H]ryanodine binding and parameter analysis. CICR activity at resting [Ca2+]cyt, A7.0, was higher in CPVT mutants than in WT and a strong inverse correlation was found between threshold [Ca2+]ER and A7.0. Interestingly, lowering RyR2 expression increased threshold [Ca2+]ER, suggesting that the threshold [Ca2+]ER depends on net Ca2+ release rate via RyR2, a product of A7.0 for each mutant and the density of RyR2 molecules. A model-based simulation successfully reproduced the [Ca2+]cyt and [Ca2+]ER changes. Interestingly, the CICR activity associated with specific mutations correlated well with the age of onset of the disease in CPVT patients carrying the mutations. Our data suggest that the reduction in threshold [Ca2+]ER for spontaneous Ca2+ release by CPVT mutation is explained by enhanced CICR activity without considering a change in the [Ca2+]ER sensitivity of RyR2.SummaryCPVT-linked RyR2 mutations are prone to induce spontaneous Ca2+ release from ER, which is strongly associated with arrhythmias. Kurebayashi et al. quantitatively explore how the changes in CICR activity by RyR2 mutations affect spontaneous Ca2+ experimentally and by model simulation.

show abstract

Section: Pathological Relevance Of Cicr Activity In Cpvt Mutationsmentioning

confidence: 82%

Section: Limitationsmentioning

confidence: 99%

Enhanced CICR activity reduces ER Ca²⁺level in cells expressing CPVT-linked mutant RyR2

Kurebayashi

Murayama

Ohta

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Catecholaminergic polymorphic VT (CPVT) is a rare cardiac ion channelopathy induced by anomalies in proteins that regulate Ca 2+ transport in heart cells that can lead to SCD[ 39 , 40 ]. CPVT is associated with mutations in the gene encoding the cardiac RyR2, a cardiac ryanodine receptor protein which is involved in calcium homeostasis and mutations in the gene that encodes calsequestrin (CASQ2), a protein that interacts with RyR2[ 39 - 41 ].…”

Section: Novel Vt Therapiesmentioning

confidence: 99%

Novel approaches for the treatment of ventricular tachycardia

Spartalis¹,

Spartalis²,

Tzatzaki³

et al. 2017

WJC

View full text Add to dashboard Cite

Ventricular tachycardia (VT) is a crucial cause of sudden cardiac death (SCD) and a primary cause of mortality and morbidity in patients with structural cardiac disease. VT includes clinical disorders varying from benign to life-threatening. Most life-threatening episodes are correlated with coronary artery disease, but the risk of SCD varies in certain populations, with various underlying heart conditions, specific family history, and genetic variants. The targets of VT management are symptom alleviation, improved quality of life, reduced implantable cardioverter defibrillator shocks, prevention of reduction of left ventricular function, reduced risk of SCD, and improved overall survival. Antiarrhythmic drug therapy and endocardial catheter ablation remains the cornerstone of guideline-endorsed VT treatment strategies in patients with structural cardiac abnormalities. Novel strategies such as epicardial ablation, surgical cryoablation, transcoronary alcohol ablation, pre-procedural imaging, and stereotactic ablative radiotherapy are an appealing area of research. In this review, we gathered all recent advances in innovative therapies as well as experimental evidence focusing on different aspects of VT treatment that could be significant for future favorable clinical applications.

show abstract

“… 128 , 129 Symptoms typically begin in childhood or adolescence, but there are cases with onset in adulthood. 130 Syncope during exercise is typically the presenting symptom. 128 Untreated, this condition has very high mortality, with reports of up to 50% by the age of 30 years.…”

Section: Catecholaminergic Polymorphic Ventricular Tachycardiamentioning

confidence: 99%

Genetics of inherited primary arrhythmia disorders

Spears¹,

Gollob²

2015

TACG

View full text Add to dashboard Cite

A sudden unexplained death is felt to be due to a primary arrhythmic disorder when no structural heart disease is found on autopsy, and there is no preceding documentation of heart disease. In these cases, death is presumed to be secondary to a lethal and potentially heritable abnormality of cardiac ion channel function. These channelopathies include congenital long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, and short QT syndrome. In certain cases, genetic testing may have an important role in supporting a diagnosis of a primary arrhythmia disorder, and can also provide prognostic information, but by far the greatest strength of genetic testing lies in the screening of family members, who may be at risk. The purpose of this review is to describe the basic genetic and molecular pathophysiology of the primary inherited arrhythmia disorders, and to outline a rational approach to genetic testing, management, and family screening.

show abstract

A novel cardiac ryanodine receptor gene (RyR2) mutation in an athlete with aborted sudden cardiac death: a case of adult-onset catecholaminergic polymorphic ventricular tachycardia

Cited by 13 publications

References 28 publications

Enhanced CICR activity reduces ER Ca²⁺level in cells expressing CPVT-linked mutant RyR2

Enhanced CICR activity reduces ER Ca²⁺level in cells expressing CPVT-linked mutant RyR2

Novel approaches for the treatment of ventricular tachycardia

Genetics of inherited primary arrhythmia disorders

Contact Info

Product

Resources

About

A novel cardiac ryanodine receptor gene (RyR2) mutation in an athlete with aborted sudden cardiac death: a case of adult-onset catecholaminergic polymorphic ventricular tachycardia

Cited by 13 publications

References 28 publications

Enhanced CICR activity reduces ER Ca2+level in cells expressing CPVT-linked mutant RyR2

Enhanced CICR activity reduces ER Ca2+level in cells expressing CPVT-linked mutant RyR2

Novel approaches for the treatment of ventricular tachycardia

Genetics of inherited primary arrhythmia disorders

Contact Info

Product

Resources

About

Enhanced CICR activity reduces ER Ca²⁺level in cells expressing CPVT-linked mutant RyR2

Enhanced CICR activity reduces ER Ca²⁺level in cells expressing CPVT-linked mutant RyR2