Vinculin variant M94I identified in sudden unexplained nocturnal death syndrome decreases cardiac sodium current.
Vinculin variant M94I identified in sudden unexplained nocturnal death syndrome decreases cardiac sodium current.
复制标题
在不明原因的夜间死亡综合征中发现的纽蛋白变异体 M94I 会降低心脏钠电流。
DOI：
10.1038/srep42953
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发表时间：
2017-02-20
影响因子：
4.6
通讯作者：
Makielski JC
中科院分区：
文献类型：
--
作者：
Cheng J;Kyle JW;Wiedmeyer B;Lang D;Vaidyanathan R;Makielski JC
不明原因夜间猝死综合征（SUNDS）是一种病因不明的尸检阴性疾病。在心肌病出现之前，VCL基因敲除小鼠的心律失常猝死与VCL（VCL）有关。我们假设VCL突变是SUNDS风险的基础。一种罕见的杂合变异VCL-M94 I在一名SUNDS受害者中发现，该受害者患有突发夜间呼吸急促，并且在已知的致喘基因中缺乏致病变异。VCL被鉴定为在体外/体内与SCN 5A相互作用。VCL-M94 I在HEK 293细胞中与心脏钠通道共表达，并且在诱导多能干细胞衍生的心肌细胞（iPSCs-CM）中也过表达。在pH 7.4的HEK 293细胞中，与WT相比，VCL-M94 I导致峰值钠电流（INa）幅度降低约30%;在睡眠呼吸暂停期间通常伴有缺氧的酸中毒条件（pH 7.0）下，与WT相比，M94 I导致峰值INa降低37%，与pH 7.4下的WT相比，VCL-M94 I和pH 7.0的组合使峰值INa降低约56%。在iPSCs-CM中，观察到M94 I对峰值INa降低的类似作用。这项研究初步表明VCL和心脏钠通道之间的物理和功能相互作用，并提出了呼吸性酸中毒在触发致命性心律失常的基础SUNDS的重要作用。
Sudden unexplained nocturnal death syndrome (SUNDS) remains an autopsy negative disorder with unclear etiology. Vinculin (VCL) was linked to sudden arrhythmia death in VCL knockout mice prior to the appearance of cardiomyopathy. We hypothesized VCL mutations underlie risk for SUNDS. A rare heterozygous variant VCL-M94I was found in a SUNDS victim who suffered sudden nocturnal tachypnea and lacked pathogenic variants in known arrhythmia-causing genes. VCL was identified to interact with SCN5A in vitro/vivo. The VCL-M94I was co-expressed with the cardiac sodium channel in HEK293 cells and also overexpressed in induced pluripotent stem cells derived cardiomyocytes (iPSCs-CM). In HEK293 cells with pH 7.4, VCL-M94I caused ~30% decrease in peak sodium current (INa) amplitude compared to WT; under acidotic conditions (pH 7.0) typically found with hypoxia during sleep apnea, M94I resulted in 37% reduction in peak INa compared to WT and the combination of VCL-M94I and pH 7.0 decreased peak INa by ~56% compared to WT at pH 7.4. In iPSCs-CM, similar effects of M94I on reduction of peak INa were observed. This study initially shows both physical and functional interaction between VCL and cardiac sodium channel, and suggests an important role for respiratory acidosis in triggering the fatal arrhythmia underlying SUNDS.