Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WI 53792, USA.
Sci Rep. 2017 Feb 20;7:42953. doi: 10.1038/srep42953.
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 (I) amplitude compared to WT; under acidotic conditions (pH 7.0) typically found with hypoxia during sleep apnea, M94I resulted in 37% reduction in peak I compared to WT and the combination of VCL-M94I and pH 7.0 decreased peak I by ~56% compared to WT at pH 7.4. In iPSCs-CM, similar effects of M94I on reduction of peak I 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.
突发性不明原因夜间死亡综合征（SUNDS）仍然是一种尸检阴性的疾病，其病因不明。在心肌病出现之前， vinculin（VCL）已与 VCL 敲除小鼠的心律失常性死亡相关。我们假设 VCL 突变是 SUNDS 的风险因素。在一名 SUNDS 受害者中发现了一种罕见的杂合变异 VCL-M94I，该患者患有突发性夜间呼吸急促，并且在已知的心律失常致病基因中没有发现致病变异。VCL 被鉴定为在体外/体内与 SCN5A 相互作用。VCL-M94I 与心脏钠通道在 HEK293 细胞中共表达，并且在诱导多能干细胞衍生的心肌细胞（iPSC-CM）中过度表达。在 pH 值为 7.4 的 HEK293 细胞中，与 WT 相比，VCL-M94I 导致峰值钠电流（I）幅度降低约 30％; 在睡眠呼吸暂停期间通常与缺氧相关的酸性条件（pH 7.0）下，M94I 导致峰值 I 比 WT 降低 37％，并且 VCL-M94I 和 pH 7.0 的组合与 pH 7.4 时的 WT 相比，峰值 I 降低了约 56％。在 iPSC-CM 中，也观察到 M94I 对降低峰值 I 的类似影响。这项研究最初表明 VCL 和心脏钠通道之间存在物理和功能相互作用，并表明呼吸性酸中毒在引发 SUNDS 潜在致命性心律失常方面具有重要作用。
