SCN1B、SCN2B基因筛查及其在扩张型心肌病心律失常中的分子机制研究

Dilated cardiomyopathy (DCM) is characterized by ventricular dilatation accompanied by ventricular systolic function decreased, eventually led to the refractory heart failure, often accompanied by atrial or ventricular arrhythmias. Disease in young adults, sudden death rate is high. General symptoms after 5 years of survival rate is about 50.0%. To data，Over 40 genes have been associated with the disease. Mutations in DCM-causing genes induce the condition through a variety of different pathological pathways with complex and not completely understood mechanisms. Mutations of SCN5A gene which encodes the alpha subunit of the major sodium channel in the heart have been demonstrated to result in myocardial damage and DCM, but the ion channel mutations cause DCM research is still less. Sodium channels by alpha and beta subunits constitute, SCN1B and SCN2B gene encoding beta 1 and beta 2 subunits. Accordingly we hypothesised that SCN1B and SCN2B mutations may also cause DCM. Current study is designed to investigate the molecular biology mechanisms of SCN1B and SCN2B gene mutations in Dilated Cardiomyopathy，by using the methods of PCR amplification and direct DNA sequencing. It is expectative to illuminate the molecular mechanisms underlined in the mechanism of SCN1B and SCN2B in DCM. These results will facilitate understanding of the biological functions of SCN1B and SCN2B, for the gene diagnosis and drug treatment of the disease to provide new train of thought.

扩张型心肌病（DCM）是一种以心室扩大并伴有心室收缩功能减退为特征的心肌病，最终导致心力衰竭，常伴有心律失常，青壮年发病，猝死率高。目前研究表明超过40个基因与DCM相关联，DCM致病基因突变诱导了各种不同的复杂病理通路，基因突变所致的DCM是近期的研究热点，然而这些机制尚未完全明确。SCN5A基因编码在钠通道α亚基，其突变已被证明可导致心肌损伤、心律失常和DCM，而SCN1B、SCN2B基因编码于β亚基，在钠离子β亚基突变引起DCM方面的研究还有待于进一步深入。我们的前期实验证实了SCN5A和SCN1B基因突变与房颤有关，据此我们提出SCN1B、SCN2B基因突变也可能引起DCM的假说，拟采用PCR扩增、DNA测序等方法，研究SCN1B、SCN2B基因突变与DCM的相关性，完善DCM的发生机理，对认识DCM的分子机制具有重要的理论意义与实际价值，为该病的基因诊断和药物治疗提供新的思路。

扩张型心肌病（DCM）是一种以心室扩大并伴有心室收缩功能减退为特征的心肌病，最终导致心力衰竭，常伴有心律失常，青壮年发病，猝死率高，目前发病机制尚未完全明确。SCN5A基因编码在钠通道α亚基，其突变已被证明可导致心肌损伤、心律失常和DCM，而SCN1B、SCN2B基因编码于β亚基，在钠离子β亚基突变引起DCM方面的研究还有待于进一步深入。我们的前期实验证实了SCN5A和SCN1B基因突变与房颤有关，DCM患者多数伴有心律失常，据此我们提出SCN1B、SCN2B基因突变也可能引起DCM的假说。本项目基本按照预定的研究目标和进度实施项目，建立984例DCM的临床诊治、个人信息数据库，发现85.77%的DCM患者存在一种或一种以上心律失常，其中以室性早搏发生率最高，其次为心房颤动。通过对142例散发性DCM患者进行全外显子基因测序分析，在7名患者SCN1B基因发现4个突变R45H、V138I、R187H、T189M，并对其基因突变危害性和保守性进行评估，R45H、V138I、R187H为有害突变，可能引起细胞钠离子通道功能改变，与DCM伴房颤密切相关。本项目在其他27例DCM伴房颤患者中发现编码在钠通道α亚基SCN5A基因6个罕见突变，SCN10A基因13个罕见突变。SCN1B、SCN5A、SCN10A基因突变可能引起钠通道功能改变使激活或失活曲线发生转移，干扰0期和复极2期的钠离子稳态，生成异常的动作电位而导致各类型心律失常，为进一步研究DCM伴心律失常发病机制提供理论和实验数据。在本项目资助下，课题组发表期刊论文7篇。培养青年骨干4名，协助培养心血管疾病基础与临床研究方向研究生2名。