心律失常相关基因MOG1的遗传和功能研究

The cardiac sodium channel α subunit Nav1.5 is critical to the generation and propagation of the action potential in the heart, and can cause lethal cardiac arrhythmias and sudden death when mutated or deregulated. Protein-protein interactions are critical for the normal function of Nav1.5, and Nav1.5 regulatory proteins have been found to be mutated in patients with inherited forms of Atrial fibrillation (AF). In 2008, our lab reported the identification of a novel protein named MOG1 interacted with Nav1.5 by using the Yeast Two-Hybrid System and demonstrated that MOG1 enhance Nav1.5 activity and stimulate it's trafficking to the cell membrane. These results support a critical role of MOG1 in regulating the cardiac sodium channel. Recently, MOG1 was described as a new disease-causing gene of Brugada syndrome. In this study, we will tested whether MOG1 could be a candidate gene for AF, and will employ gene knockout technology in animal to investigate the physiological roles of MOG1 and potential pathophysiological mechanisms of the MOG1 related cardiac channelopathy.

心脏钠通道的α亚基Nav1.5在心脏动作电位的产生和传导过程中起着重要的作用，其基因突变会导致包括房颤在内的不同类型心律失常或猝死，近年来也陆续发现多个编码与Nav1.5相互作用蛋白的基因突变与心律失常疾病发生相关。MOG1是我们最近通过酵母双杂交技术鉴定出来的与Nav1.5相互作用蛋白，它对心肌Nav1.5通道的生理功能具有重要调节作用。MOG1基因突变可导致心律失常，目前已经发现MOG1突变引起Brugada综合征，但MOG1变异是否与其它类型心律失常如房颤发生相关尚不清楚。针对这一问题，在本研究中我们将在房颤病人群体中进行MOG1基因遗传突变筛选和突变功能分析；此外由于MOG1本身在心脏中的正常生理功能以及具体病理机制尚不完全清楚，本研究拟采用MOG1基因敲除动物模型分析MOG1在心脏中的生理作用并阐明MOG1相关心律失常疾病的分子发病机制。

Mog1是我们最近鉴定出来的与心脏钠通道的α亚基Nav1.5相互作用的蛋白，并对Nav1.5生理功能具有重要调节作用。而且Mog1突变通过影响Nav1.5功能可导致心律失常如Brugada综合征的发生，但具体分子病理机制不清楚。在本研究中我们采用Mog1基因敲除小鼠模型分析Mog1在心脏中的生理作用并探索Mog1相关心律失常疾病的分子发病机制。我们发现Mog1纯合敲除鼠生长发育情况基本正常，有繁殖能力，生活习性无明显异常。纯合敲除鼠无明显心律失常事件的发生，但纯合敲除鼠QRS明显延长；纯合敲除小鼠心脏Nav1.5 mRNA表达正常，Nav1.5总蛋白和细胞膜Nav1.5蛋白表达均未出现明显变化；与对照组相比，纯合敲除小鼠心肌细胞钠通道电流密度未见明显的变化；心脏超声检测发现敲除鼠的左室收缩/舒张末期直径及体积明显增大，射血分数和缩短分数明显降低；病理检测发现心脏未出现明显扩张或肥厚，HE染色和Masson染色整体也未见明显异常。综上所述，我们的研究初步揭示了Mog1在心脏中所起的重要作用。