A de novo gain-of-function KCND3 mutation in early repolarization syndrome
A de novo gain-of-function KCND3 mutation in early repolarization syndrome
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DOI：
10.1016/j.hrthm.2019.05.033
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发表时间：
2019-11-01
期刊：
影响因子：
5.5
通讯作者：
Horie, Minoru
中科院分区：
文献类型：
--
作者：
Takayama, Koichiro;Ohno, Seiko;Horie, Minoru
早期复极综合征（ERS）的特征是心电图J点抬高和心室颤动（VF）。早期复极是由心肌动作电位跨壁电梯度的增大引起的，因此瞬时外向钾电流（I-to）被认为是阐明ERS机制的关键候选电流。KCND 3编码Kv4.3，I-to通道的α亚基，目的寻找与ERS相关的新的KCND 3突变，阐明其发病机制。方法对11例无亲缘关系的ERS先证者进行基因筛查，并对检测到的突变进行电生理特性分析。结果在1例先证者中发现了一种新的KCND 3基因的新杂合突变Gly 306 Ala（c.917g>c）。先证者是一名12岁的男孩，他患有VF风暴，并在多个导联中显示出显著的J点抬高。静脉注射异丙肾上腺素和随后的奎尼丁管理有效地防止VF复发和恢复J点抬高。在电生理学分析中，表达突变体Kv4.3的培养细胞与野生型相比显示出显著增加的电流密度、缓慢失活和从失活缓慢恢复。奎尼丁的细胞外应用显着恢复失活的时间过程中突变体Kv4.3。模拟研究证实了新的KCND 3突变与心电图早期复极的关系。结论发现一种新的KCND 3杂合突变与ERS相关。其发病机制可以用I-to增加来解释。KCND 3基因筛查有助于了解该病的发病机制和选择有效的治疗方法。
BACKGROUND Early repolarization syndrome (ERS) is characterized by J-point elevation on electrocardiograms and ventricular fibrillation (VF). Early repolarization arises from augmentation of the transmural electrical gradient in the cardiac action potential; therefore, the transient outward potassium current (I-to) has been regarded as a key candidate current for elucidating the mechanism of ERS. KCND3 encoding Kv4.3, an alpha-subunit of the I-to channel, is considered as one of target genes.OBJECTIVE The purpose of this study was to search for novel KCND3 mutations associated with ERS and to clarify the pathogenesis.METHODS We performed genetic screening for 11 unrelated probands with ERS and analyzed the electrophysiological properties of detected mutations by patch-damp methods.RESULTS A novel de novo KCND3 heterozygous mutation, Gly306Ala (c.917g>c), was found in 1 proband. The proband was a 12-year-old boy, who suffered VF storm and showed significant J-point elevation in multiple leads. Intravenous isoproterenol and subsequent administration of quinidine were effective in preventing VF recurrence and restored the J-point elevation. In electrophysiological analysis, cultured cells expressing mutant Kv4.3 showed significantly increased current densities, slow inactivation, and slow recovery from inactivation compared to wild type. Extracellular application of quinidine significantly restored the inactivation time course in mutant Kv4.3. A simulation study confirmed the relationship between the novel KCND3 mutation and early repolarization on electrocardiograms.CONCLUSION A novel KCND3 heterozygous mutation was found to be associated with ERS. The pathogenesis can be explained by the increased I-to. Genetic screening for KCND3 could be useful for understanding the pathogenesis and selecting effective treatment.