Background

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic syndrome and a cause of exercise-related sudden death. CPVT has been reported to be caused by gain of function underlying a mutation of cardiac ryanodine receptor (RyR2).

Methods

In a family with a CPVT patient, genomic DNA was extracted from peripheral blood lymphocytes, and the RyR2 gene underwent target gene sequence using MiSeq. The activity of wild-type (WT) and mutant RyR2 channel were evaluated by monitoring Ca²⁺ signals in HEK293 cells expressing WT and mutant RyR2. We investigated a role of a RyR2 mutation in the recent tertiary structure of RyR2.

Results

Though a 17-year-old man diagnosed as CPVT had implantable cardioverter defibrillator (ICD) and was going to undergo catheter ablation for the control of paroxysmal atrial fibrillation, he suddenly died at the age of twenty-one because of ventricular fibrillation which was spontaneously developed after maximum inappropriate ICD shocks against rapid atrial fibrillation. The genetic test revealed a de novo RyR2 mutation, Gln4936Lys in mosaicism which was located at the α-helix interface between U-motif and C-terminal domain. In the functional analysis, Ca²⁺ release from endoplasmic reticulum via the mutant RyR2 significantly increased than that from WT.

Conclusion

A RyR2 mutation, Gln4936Lys, to be documented in a CPVT patient with exercise-induced ventricular tachycardias causes an excessive Ca²⁺ release from the sarcoplasmic reticulum which corresponded to clinical phenotypes of CPVT. The reduction of inappropriate shocks of ICD is essential to prevent unexpected sudden death in patients with CPVT.

中文翻译：

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一例具有新型 RyR2 突变的儿茶酚胺能多形性室性心动过速病例中植入式心脏复律除颤器不当电击后猝死

背景

儿茶酚胺能多形性室性心动过速 (CPVT) 是一种遗传性致心律失常综合征，是运动相关性猝死的原因。据报道，CPVT 是由心脏兰尼碱受体 ( RyR2 ) 突变导致的功能获得引起的。

方法

在一个有 CPVT 患者的家庭中，从外周血淋巴细胞中提取基因组 DNA，并使用 MiSeq 对 RyR2 基因进行靶基因序列。野生型 (WT) 和突变型RyR2通道的活性通过监测表达 WT 和突变型RyR2的 HEK293 细胞中的 Ca ²⁺信号来评估。我们研究了 RyR2 突变在最近的 RyR2 三级结构中的作用。

结果

一名被诊断为 CPVT 的 17 岁男子安装了植入式心律转复除颤器 (ICD)，并准备进行导管消融以控制阵发性心房颤动，但他在 21 岁时突然死于自发性心室颤动在针对快速心房颤动的最大不适当 ICD 电击后发展。基因测试揭示了一个新的 RyR2 突变，Gln4936Lys 嵌合体，位于 U 基序和 C 末端结构域之间的 α-螺旋界面。在功能分析中，通过突变体RyR2从内质网释放的Ca ²⁺显着高于来自WT的释放。

结论

在患有运动性室性心动过速的 CPVT 患者中记录的 RyR2 突变 Gln4936Lys 导致肌浆网释放过多的 Ca ^{2+ ，这与 CPVT 的临床表型相对应。}减少 ICD 的不当电击对于防止 CPVT 患者意外猝死至关重要。