An East Asian Common Variant Vinculin P.Asp841His Was Associated With Sudden Unexplained Nocturnal Death Syndrome in the Chinese Han Population.
An East Asian Common Variant Vinculin P.Asp841His Was Associated With Sudden Unexplained Nocturnal Death Syndrome in the Chinese Han Population.
复制标题
东亚常见变体纽蛋白 P.Asp841His 与中国汉族人群不明原因夜间死亡综合征有关。
DOI：
10.1161/jaha.116.005330
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发表时间：
2017-04-03
影响因子：
5.4
通讯作者：
Makielski JC
中科院分区：
文献类型：
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作者：
Cheng J;Kyle JW;Lang D;Wiedmeyer B;Guo J;Yin K;Huang L;Vaidyanathan R;Su T;Makielski JC
我们已经确定心肌病易感基因纽蛋白 (VCL) 突变 M94I 可能是不明原因夜间死亡综合征 (SUNDS) 病例的原因。我们讨论了 VCL 常见变体 D841H 是否与 SUNDS 相关。在 120 个 SUNDS 病例中的 8 个病例中，我们检测到东亚常见的 VCL 变体 p.Asp841His (D841H)。将本地数据库中一般人群的 H841 等位基因频率（1818 例中的 15 例）与 SUNDS 受害者（240 例中的 10 例）进行比较，得出 SUNDS 的比值比为 5.226（95% CI，2.321，11.769）。 VCL-D841H 变体经过工程改造，在 HEK293 细胞中与心脏钠通道 (SCN5A) 共表达，或在人诱导多能干细胞衍生的心肌细胞中过表达，以使用全细胞膜片钳方法检查其对钠通道功能的影响。在 HEK293 细胞中，在生理 pH 条件（pH 7.4）下，与野生型（WT）相比，D841H 导致峰值 IN a 幅度降低 29%，而在酸中毒条件（pH 7.0）下，与 pH 7.4 的 WT 相比，D841H 进一步降低至 43%，同时失活显着负移。在诱导多能干细胞衍生的心肌细胞中，观察到 D841H 对 IN a 的类似作用。 VCL 与 SCN5A 共定位于人心肌细胞的闰盘处。 VCL 也被证实与 SCN5A 直接相互作用，并且 VCL-D841H 不会破坏 VCL 和 SCN5A 的结合。 VCL 常见变异在遗传和生物物理上与中国 SUNDS 相关。酸中毒时 VCL-D841H 引起的 SCN5A 功能丧失加剧，支持酸中毒的夜间睡眠呼吸障碍可能在 SUNDS 的发病机制中发挥关键作用。
We have identified the cardiomyopathy‐susceptibility gene vinculin (VCL) mutation M94I may account for a sudden unexplained nocturnal death syndrome (SUNDS) case. We addressed whether VCL common variant D841H is associated with SUNDS. In 8 of 120 SUNDS cases, we detected an East Asian common VCL variant p.Asp841His (D841H). Comparing the H841 allele frequency of the general population in the local database (15 of 1818) with SUNDS victims (10 of 240) gives an odds ratio for SUNDS of 5.226 (95% CI, 2.321, 11.769). The VCL‐D841H variant was engineered and either coexpressed with cardiac sodium channel (SCN5A) in HEK293 cells or overexpressed in human induced pluripotent stem‐cell–derived cardiomyocytes to examine its effects on sodium channel function using the whole‐cell patch‐clamp method. In HEK293 cells, under physiological pH conditions (pH 7.4), D841H caused a 29% decrease in peak IN a amplitude compared to wild type (WT), whereas under acidotic conditions (pH 7.0), D841H decreased further to 43% along with significant negative shift in inactivation compared to WT at pH 7.4. In induced pluripotent stem‐cell‐derived cardiomyocytes, similar effects of D841H on IN a were observed. VCL colocalized with SCN5A at the intercalated disk in human cardiomyocytes. VCL was also confirmed to directly interact with SCN5A, and VCL‐D841H did not disrupt the association of VCL and SCN5A. A VCL common variant was genetically and biophysically associated with Chinese SUNDS. The aggravation of loss of function of SCN5A caused by VCL‐D841H under acidosis supports that nocturnal sleep respiratory disorders with acidosis may play a key role in the pathogenesis of SUNDS.