Telethonin variants found in Brugada syndrome, J-wave pattern ECG, and ARVC reduce peak Nav 1.5 currents in HEK-293 cells
Telethonin variants found in Brugada syndrome, J-wave pattern ECG, and ARVC reduce peak Nav 1.5 currents in HEK-293 cells
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Brugada 综合征、J 波型心电图和 ARVC 中发现的 Telethonin 变异可降低 HEK-293 细胞中的峰值 Nav 1.5 电流
DOI：
10.1111/pace.13996
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Ai T
中科院分区：
文献类型：
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作者：
Turker I;Makiyama T;Ueyama T;Shimizu A;Yamakawa M;Chen PS;Vatta M;Horie M;Ai T
背景Telethonin（TCAP）是一种维持心肌细胞骨架完整性和多种信号通路的Z盘蛋白，它通过直接作用调节人心肌钠通道α亚基（hNav1.5）。在心肌病中发现了几种TCAP变体。我们试图调查是否TCAP变异与心律失常syndrome.MethodsMutational analyses forTCAP进行了303例日本患者Brugada综合征，致心律失常性右心室心肌病，和J-波型心电图。采用膜片钳技术，在稳定表达hNav1.5并瞬时转染野生型（WT）或变体TCAP.ResultsWe鉴定了两种TCAP变体，c.145G>A：p.E49K和c.458G> A：p.R153H，在四个个体中研究了hNav1.5的电生理特性。在2例ARVC或BrS患者中发现p.E49K。在2例BrS或J波型ECG患者中发现p.R153H。没有患者具有变异hNav1.5。膜片钳实验表明，与WT‐TCAP相比，表达p.R153H和p.E49K的细胞中峰值钠电流显著降低（66%，p.R153H; 72%，p.E49K）。与WT-TCAP相比，表达p.E49K的细胞中IV峰曲线的电压依赖性发生了5 mV的位移。p.R153 H不使hNav 1. 5的电压依赖性激活发生漂移，而p.E49 K使hNav 1. 5的电压依赖性稳态失活发生漂移。结论我们在BrS患者中发现了两种TCAP变异体，即J波型ECG和ARVC，它们可导致hNav 1. 5在异源表达系统中的功能丧失。我们的观察表明这些变异可能损害INa并与患者的电生理表型相关。进一步的研究将我们的实验数据与临床表型联系起来是必要的。
BackgroundTelethonin (TCAP) is a Z‐disk protein that maintains cytoskeletal integrity and various signaling pathways in cardiomyocytes.TCAPis shown to modulate α‐subunit of the human cardiac sodium channel (hNav1.5) by direct interactions. SeveralTCAPvariants are found in cardiomyopathies. We sought to investigate whether TCAP variants are associated with arrhythmia syndromes.MethodsMutational analyses forTCAPwere performed in 303 Japanese patients with Brugada syndrome, arrhythmogenic right ventricular cardiomyopathy, and J‐wave pattern ECG. Using patch‐clamp techniques, electrophysiological characteristics of hNav1.5 were studied in HEK‐293 cells stably expressing hNav1.5 and transiently transfected with wild‐type (WT) or variantTCAP.ResultsWe identified twoTCAPvariants, c.145G>A:p.E49K and c.458G>A:p.R153H, in four individuals. p.E49K was found in two patients with ARVC or BrS. p.R153H was found in two patients with BrS or J‐wave pattern ECG. No patient had variant hNav1.5. Patch‐clamp experiments demonstrated that peak sodium currents were significantly reduced in cells expressing p.R153H and p.E49K compared with WT‐TCAP(66%, p.R153H; 72%, p.E49K). Voltage dependency of peak IV curve was rightward‐shifted by 5 mV in cells expressing p.E49K compared with WT‐TCAP. Voltage dependency of activation was not leftward‐shifted by p.R153H, while voltage dependency of steady‐state inactivation was leftward‐shifted by p.E49K.ConclusionsWe found twoTCAPvariants in the patients with BrS, J‐wave pattern ECG, and ARVC that can cause loss‐of‐function of the hNav1.5 in heterologous expression systems. Our observation suggests that these variants might impair INaand be associated with the patients’ electrophysiological phenotypes. Further studies linking our experimental data to clinical phenotypes are warranted.