Identification of transmembrane protein 168 mutation in familial Brugada syndrome.
Identification of transmembrane protein 168 mutation in familial Brugada syndrome.
复制标题
家族性 Brugada 综合征跨膜蛋白 168 突变的鉴定。
DOI：
10.1096/fj.201902991r
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发表时间：
2020
期刊：
影响因子：
4.8
通讯作者：
Ogita H.
中科院分区：
文献类型：
--
作者：
Shimizu A;Zankov DP;Sato A;Komeno M;Toyoda F;Yamazaki S;Makita T;Noda T;Ikawa M;Asano Y;Miyashita Y;Takashima S;Morita H;Ishikawa T;Makita N;Hitosugi M;Matsuura H;Ohno S;Horie M;Ogita H.
Brugada综合征（BrS）是一种遗传性通道病，在非结构性心脏病患者中，几乎20%的心脏性猝死是由BrS引起的。大约70%的BrS患者的致病基因突变仍然未知。在这项研究中，我们使用全外显子组测序来调查临床诊断为BrS的家族中的候选突变。在有症状个体的跨膜蛋白168（TMEM 168）基因中鉴定出杂合的1616 G>A替换（R539 Q突变）。与内源性TMEM 168类似，在HL-1细胞中异位诱导的TMEM 168野生型（WT）和突变体蛋白均显示核膜定位。在表达突变型TMEM 168的HL-1心肌细胞中观察到Na+电流和Nav1.5蛋白表达显著降低。通过药理学刺激在异源Tmem 1681616 G>A基因敲入小鼠中诱导室性快速性心律失常和传导障碍，但在WT小鼠中未诱导。在从Tmem 168敲入心脏分离的心室肌细胞中，Na+电流减少，Nav1.5表达也受损。这种损伤依赖于Nedd 4 - 2与Nav1.5结合的增加和随后的泛素化。总的来说，我们的研究结果显示了TMEM 1681616 G>A突变与BrS家族中的乳腺癌发生之间的关联。
Brugada syndrome (BrS) is an inherited channelopathy responsible for almost 20% of sudden cardiac deaths in patients with nonstructural cardiac diseases. Approximately 70% of BrS patients, the causative gene mutation(s) remains unknown. In this study, we used whole exome sequencing to investigate candidate mutations in a family clinically diagnosed with BrS. A heterozygous 1616G>A substitution (R539Q mutation) was identified in the transmembrane protein 168 (TMEM168) gene of symptomatic individuals. Similar to endogenous TMEM168, both TMEM168 wild‐type (WT) and mutant proteins that were ectopically induced in HL‐1 cells showed nuclear membrane localization. A significant decrease in Na+current and Nav1.5 protein expression was observed in HL‐1 cardiomyocytes expressing mutant TMEM168. Ventricular tachyarrhythmias and conduction disorders were induced in the heterozygousTmem1681616G>A knock‐in mice by pharmacological stimulation, but not in WT mice. Na+current was reduced in ventricular cardiomyocytes isolated from theTmem168knock‐in heart, and Nav1.5 expression was also impaired. This impairment was dependent on increased Nedd4‐2 binding to Nav1.5 and subsequent ubiquitination. Collectively, our results show an association between theTMEM1681616G>A mutation and arrhythmogenesis in a family with BrS.