Loss-of-function mutations in cardiac ryanodine receptor channel cause various types of arrhythmias including long QT syndrome
Loss-of-function mutations in cardiac ryanodine receptor channel cause various types of arrhythmias including long QT syndrome
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DOI：
10.1093/europace/euab250
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发表时间：
2021-10-18
期刊：
影响因子：
6.1
通讯作者：
Ohno, Seiko
中科院分区：
文献类型：
--
作者：
Hirose, Sayako;Murayama, Takashi;Ohno, Seiko
编码心脏兰尼碱受体通道 (RyR2) 的 RYR2 的功能获得性突变会导致儿茶酚胺能多形性室性心动过速 (CPVT)。然而，由于分析的突变数量较少，功能丧失突变的基因型-表型相关性仍然未知。在这项研究中，我们旨在研究 RYR2 功能丧失突变患者的基因型与表型相关性。方法和结果 我们对 710 名 16 岁以下患有遗传性原发性心律失常综合征 (IPAS) 的先证者进行了靶向基因测序。在 63 名先证者中鉴定出 RYR2 突变，其中 3 名先证者表现出与 CPVT 不同的临床特征。 p.E4146D 的先证者出现心室颤动 (VF) 和 QT 延长，而 p.S4168P 的先证者则出现 QT 延长和心动过缓。另一个患有 p.S4938F 的先证者表现出尖端扭转型室性心动过速 (scTdP) 的短耦合变异。为了评估先前报道的长 QT 综合征 (LQTS) 中这三个突变体 RyR2 和 p.K4594Q 的功能改变，我们测量了 HEK293 细胞和 HL-1 心肌细胞中的 Ca2+ 信号以及 Ca2+ 依赖性 [H-3]ryanodine 结合。所有突变体 RyR2 均表现出 Ca2+ 释放减少、内质网 Ca2+ 增加和 [H-3]ryanodine 结合减少，表明功能丧失。在 HL-1 细胞中，S4168P 和 K4594Q 的外源表达降低了 Ca2+ 瞬变幅度，但不诱导 Ca2+ 波，而 E4146D 和 S4938F 的表达则诱发频繁的局部 Ca2+ 波。结论 RYR2 功能丧失突变可能与多种类型的心律失常有关，包括 LQTS、VF 和 scTdP，具体取决于通道活性的改变。在临床上不同于 CPVT 的 IPAS 患者中搜索 RYR2 突变将是有效发现功能丧失的 RYR2 突变的有用策略。
Aims Gain-of-function mutations in RYR2, encoding the cardiac ryanodine receptor channel (RyR2), cause catecholaminergic polymorphic ventricular tachycardia (CPVT). Whereas, genotype-phenotype correlations of loss-of-function mutations remains unknown, due to a small number of analysed mutations. In this study, we aimed to investigate their genotype-phenotype correlations in patients with loss-of-function RYR2 mutations. Methods and results We performed targeted gene sequencing for 710 probands younger than 16-year-old with inherited primary arrhythmia syndromes (IPAS). RYR2 mutations were identified in 63 probands, and 3 probands displayed clinical features different from CPVT. A proband with p.E4146D developed ventricular fibrillation (VF) and QT prolongation whereas that with p.S4168P showed QT prolongation and bradycardia. Another proband with p.S4938F showed short-coupled variant of torsade de pointes (scTdP). To evaluate the functional alterations in these three mutant RyR2s and p.K4594Q previously reported in a long QT syndrome (LQTS), we measured Ca2+ signals in HEK293 cells and HL-1 cardiomyocytes as well as Ca2+-dependent [H-3]ryanodine binding. All mutant RyR2s demonstrated a reduced Ca2+ release, an increased endoplasmic reticulum Ca2+, and a reduced [H-3]ryanodine binding, indicating loss-of-functions. In HL-1 cells, the exogenous expression of S4168P and K4594Q reduced amplitude of Ca2+ transients without inducing Ca2+ waves, whereas that of E4146D and S4938F evoked frequent localized Ca2+ waves. Conclusion Loss-of-function RYR2 mutations may be implicated in various types of arrhythmias including LQTS, VF, and scTdP, depending on alteration of the channel activity. Search of RYR2 mutations in IPAS patients clinically different from CPVT will be a useful strategy to effectively discover loss-of-function RYR2 mutations.