AKAP10与汉族人群病窦综合征的关联研究及其新的突变型致病窦的机制研究
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摘要
缓慢性心律失常是临床上严重威胁人民健康的致死致残疾病之一,主要包括窦房结自律性受损和传导阻滞,临床上两者常常合并存在。其中,尤其以病窦综合征最为常见。病态窦房结综合征是因窦房结节律功能紊乱而导致的一种心律失常,每年因患病态窦房结综合征而做心脏起搏器手术的约占总心脏起搏器例数的50%。病态窦房结综合征在临床上主要表现为窦性心律不齐(过缓、过速或二者合并存在),其病因多种多样,目前发病机制并不明确,人们对病窦综合征发病机制的认识主要集中在以下三个方面：(1)离子通道基因表达的改变；(2)窦房结细胞的减少；(3)结缔组织的主要成分的累积。其中,遗传因素导致的离子通道基因表达的改变多见于国外研究报道,如HCN4,SCN5A等突变导致的病窦家系的报道,然而,针对这些离子通道进行生物起搏的研究结果并不如预料的那么理想,这提示还有很多新的病窦相关基因有待发现。因此,对病窦综合征进行遗传学研究,有助于揭示疾病的致病机制,为发现病窦有效的治疗靶点和进行生物起搏研究提供依据。本课题运用分子生物学、细胞生物学、动物实验以及遗传学的手段,系统地探讨了一个A型激酶锚定蛋白AKAP10在病窦综合征的发病过程中的作用,并探讨了其分子机制。具体包括以下两部分研究结果：
1. AKAP10与中国汉族人群病窦综合征的关联研究病窦综合征占植入心脏起搏器手术病因的一半以上,然而大多数病窦综合征的致病基因和机制尚不清楚。我们通过大量检索文献确定了4个跟心律失常发生密切相关的基因(AKAP10, Kcnj8, Cacnald, MIR-1)作为候选基因,利用PCR-SSCP和直接测序法确定了AKAP10的多个位点的改变与窦性停搏密切相关。我们首先收集了456例病态窦房结综合征的患者(其中包含227例窦性停搏患者),467例对照样品,用PCR-SSCP筛选和直接测序法在窦性停搏患者中发现并鉴定了2个AKAP10新突变：位于Exon4的c.682_687delAGAACT (p.Arg228_Thr229del)和位于Intron6的c.1062-2A>G。而且通过关联分析的方法证实AKAP10中两个SNP位点rs203462和rs4925060与窦性停搏有统计学意义上的相关性。本研究首次在窦性停搏患者中发现AKAP10的多个位点(其中包含2个新的突变位点及2个SNP位点)改变,提示AKAP10这一基因可能参与了病窦综合征尤其是窦性停搏的发生发展。
2.新的突变型AKAP10致病窦的机制研究我们构建AKAP10的微基因进行研究,发现并证明位于AKAP10Intron6的c.1062-2A>G突变可导致RNA剪接异常,造成EXON7的缺失,推测这可能是该突变导致病窦发生的机制。我们进一步对人的不同的细胞系包括人脐静脉内皮细胞(HUVEC),人主动脉平滑肌细胞(HASMC),人单核细胞系(THP-1)以及多个患者的心肌组织,检测了AKAP10的转录本表达情况,首次发现人的AKAP10存在两个转录本(含有EXON7及缺失EXON7),在不同的组织细胞中AKAP10表达的转录本情况是不同的,但是人的心肌中AKAP10只有一种转录本(含有EXON7),提示这种缺失EXON7的转录本可能是导致病窦发生的机制,很有可能AKAP10不同的转录本的功能是不同的。
为了从功能上证明位于Exon4的c.682_687delAGAACT(p. Arg228_Thr229del)AKAP10新突变可以导致病窦,我们课题组创建了国际上首个停跳状态下的早期(3dpf)斑马鱼心电图检测平台,并用注射RNA的方法在过表达p. Arg228_Thr229del突变体的斑马鱼中成功模拟出窦性停搏样表型。我们进一步在HEK293A细胞中同时过表达p. Arg228_Thr229del突变体和HCN4/HCN2,利用激光共聚焦显微镜检测到与野生型相比,突变型AKAP10(p. Arg228_Thr229del)可以减弱HCN4的上膜,提示p. Arg228_Thr229del突变体可能就是通过减弱HCN4的上膜影响了窦房结细胞膜HCN4的表达,使得起搏电流If减弱,从而导致了病窦的发生。
综合两部分研究内容,我们通过对A型激酶锚定蛋白AKAP10的遗传分析和功能探讨,首次发现它对HCN4细胞膜表达的调控作用,提示AKAP10可能通过某种机制参与了窦房结细胞内HCN4的trafficking过程。该结果加深了我们对相关病窦综合征疾病发病机制的认识,并为病窦综合征的临床诊治提供了新的理论依据。
Bradyarrhythmia is one of the serious threat to people' s health clinic lethal diseases, including damage to the sinus node automaticity and atrial-ventricular block, both clinically often in combination. Among them, especially sick sinus syndrome is most common. Sick sinus syndrome is a cardiac arrhythmia caused by sinus rhythm dysfunction and accounts for more than a half of patients undergo pacemaker transplantation. The major clinical manifestations of sick sinus syndrome is sinus arrhythmia (including bradycardia, tachycardia, or both in combination), and its etiology is various, also pathogenesis is not clear at present. The understanding of its pathogenesis mainly focused on the following three aspects:(1) abnormal gene expression of ion channels;(2) reduction of the sinus node cells;(3) cumulative component of connective tissue. Among them, the changes in ion channel gene expression caused by genetic factors are common, which is mainly reported in foreign documents. For example, the mutations of HCN4, SCN5A, etc. However, the progress in biological pacemaker is not ideal as expected, which suggests that there are a lot of new sick sinus syndrome-related genes remain to be discovered. Therefore, the genetic research in sick sinus syndrome will contribute to reveal the pathogenesis of sinus node dysfunction and provide the basis for effective treatment of and biological pacemaker study. Our study systematically explore the role of A-kinase anchoring protein AKAP10in the pathogenesis of sick sinus syndrome, and also analyze its molecular mechanism, with the methods of molecular biology, cell biology, and genetics. Our main findings are:
1. Genetic associaton study of AKAP10with sinus node dysfunction in Han Chinese population
Sick sinus syndrome accounts for more than a half of the implantable cardiac pacemaker surgery, however, the mechanisms of sick sinus syndrome is still unclear. We determined based on a large number of documents retrieved arrhythmia with four closely related genes (AKAP10, Kcnj8, Cacnald, MIR-1) as candidate genes using the PCR-SSCP and direct sequencing methods and finaly determined several SNPs of AKAP10are associated with sinus arrest Firsly we collected456cases with sick sinus syndrome (which including227patients with sinus arrest) and467control. By PCR-SSCP and direct sequencing, we two novel AKAP10mutations:c.682_687delAGAACT (p. Arg228_Thr229de1) in exon4and c.1062-2A> G in intron6. And we also found two SNPs (rs203462and rs4925060) are both significantly correlated with sinus node dysfunction. In summary, we for the first time found two novel AKAP10mutations and two SNPs in sinus node dysfunction patients, which indicates that the AKAP10gene may be involved in the mechanism of sinus node dysfunction, especially in the occurrence of sinus arrest.
The first study found that in patients with sinus arrest AKAP10multiple sites (which contains two new mutations and two SNP loci) change, suggesting that this gene may be involved in AKAP10sick sinus syndrome, especially occurrence of sinus arrest development.
2. The Mechanism of novel mutations of AKAP10associated with sinus node dysfuntion
We constructed the micro gene of AKAP10to prove that the novel mutation c.1062-2A> G in intron6of AKAP10can lead to abnormal RNA splicing, resulting in missing exon7, which may be the possible mechanism of sinus node dysfunction. We detected the transcrips of AKAP10in different human cell lines, including human umbilical vein endothelial cells (HUVEC), human aortic smooth muscle cells (HASMC), human monocytic cell line (THP-1) and myocardial samples from several patients. We found different transcripts of AKAP10in different cell lines (containing exon7or missing exon7),but in the myocardium we found only one transcript of AKAP10(containing exon7), which indicate that the lack of exon7in AKAP10may lead to sick sinus syndrome, and different transcripts of AKAP10may vary in function.
To prove the novel mutation c.682_687delAGAACT (p. Arg228_Thr229de1) in exon4of AKAP10can lead to sinus node dysfunction, we established the earlier (3dpf) zebrafish electrocardiogram detection platform, by injected the RNA to overpressed p. Arg228_Thr229del and then successfully simulated the sinus arrest-like phenotype. We further overexpressed p. Arg228_Thr229del and HCN4/HCN2in HEK293A, and then using the confocol microscopy scaning. Finally we found that compared to the wild type group, the mutant group (p. Arg228_Thr229del) can reduced the expression of HCN4in membrane, which may be the mechanism of occurrence of sinus node dysfunction.
Takern together, by genetic and functional study on AKAP10, we found its essenpial role in regulating the expression of HCN4in membrane, suggesting that AKAP10is possibly involved in the pathogenesis of sinus node dysfunction. The new discoveries would refresh our knowledge in the occurrence and development of sinus node dysfunction and provided new theoretical
Comprehensive two-part research, we adopted the A-type kinase anchoring protein AKAP10investigate genetic and functional analysis, first found its role in regulating the expression of HCN4membrane, suggesting that AKAP10possibly through a mechanism involved in the sinoatrial node cells HCN4trafficking process. The results deepen our understanding of the pathogenesis of diseases associated with sick sinus syndrome, and for the clinical diagnosis and treatment of sick sinus syndrome provides a new theoretical basis for clinical diagnosis and treatment.
1. AKAP10与中国汉族人群病窦综合征的关联研究病窦综合征占植入心脏起搏器手术病因的一半以上,然而大多数病窦综合征的致病基因和机制尚不清楚。我们通过大量检索文献确定了4个跟心律失常发生密切相关的基因(AKAP10, Kcnj8, Cacnald, MIR-1)作为候选基因,利用PCR-SSCP和直接测序法确定了AKAP10的多个位点的改变与窦性停搏密切相关。我们首先收集了456例病态窦房结综合征的患者(其中包含227例窦性停搏患者),467例对照样品,用PCR-SSCP筛选和直接测序法在窦性停搏患者中发现并鉴定了2个AKAP10新突变：位于Exon4的c.682_687delAGAACT (p.Arg228_Thr229del)和位于Intron6的c.1062-2A>G。而且通过关联分析的方法证实AKAP10中两个SNP位点rs203462和rs4925060与窦性停搏有统计学意义上的相关性。本研究首次在窦性停搏患者中发现AKAP10的多个位点(其中包含2个新的突变位点及2个SNP位点)改变,提示AKAP10这一基因可能参与了病窦综合征尤其是窦性停搏的发生发展。
2.新的突变型AKAP10致病窦的机制研究我们构建AKAP10的微基因进行研究,发现并证明位于AKAP10Intron6的c.1062-2A>G突变可导致RNA剪接异常,造成EXON7的缺失,推测这可能是该突变导致病窦发生的机制。我们进一步对人的不同的细胞系包括人脐静脉内皮细胞(HUVEC),人主动脉平滑肌细胞(HASMC),人单核细胞系(THP-1)以及多个患者的心肌组织,检测了AKAP10的转录本表达情况,首次发现人的AKAP10存在两个转录本(含有EXON7及缺失EXON7),在不同的组织细胞中AKAP10表达的转录本情况是不同的,但是人的心肌中AKAP10只有一种转录本(含有EXON7),提示这种缺失EXON7的转录本可能是导致病窦发生的机制,很有可能AKAP10不同的转录本的功能是不同的。
为了从功能上证明位于Exon4的c.682_687delAGAACT(p. Arg228_Thr229del)AKAP10新突变可以导致病窦,我们课题组创建了国际上首个停跳状态下的早期(3dpf)斑马鱼心电图检测平台,并用注射RNA的方法在过表达p. Arg228_Thr229del突变体的斑马鱼中成功模拟出窦性停搏样表型。我们进一步在HEK293A细胞中同时过表达p. Arg228_Thr229del突变体和HCN4/HCN2,利用激光共聚焦显微镜检测到与野生型相比,突变型AKAP10(p. Arg228_Thr229del)可以减弱HCN4的上膜,提示p. Arg228_Thr229del突变体可能就是通过减弱HCN4的上膜影响了窦房结细胞膜HCN4的表达,使得起搏电流If减弱,从而导致了病窦的发生。
综合两部分研究内容,我们通过对A型激酶锚定蛋白AKAP10的遗传分析和功能探讨,首次发现它对HCN4细胞膜表达的调控作用,提示AKAP10可能通过某种机制参与了窦房结细胞内HCN4的trafficking过程。该结果加深了我们对相关病窦综合征疾病发病机制的认识,并为病窦综合征的临床诊治提供了新的理论依据。
Bradyarrhythmia is one of the serious threat to people' s health clinic lethal diseases, including damage to the sinus node automaticity and atrial-ventricular block, both clinically often in combination. Among them, especially sick sinus syndrome is most common. Sick sinus syndrome is a cardiac arrhythmia caused by sinus rhythm dysfunction and accounts for more than a half of patients undergo pacemaker transplantation. The major clinical manifestations of sick sinus syndrome is sinus arrhythmia (including bradycardia, tachycardia, or both in combination), and its etiology is various, also pathogenesis is not clear at present. The understanding of its pathogenesis mainly focused on the following three aspects:(1) abnormal gene expression of ion channels;(2) reduction of the sinus node cells;(3) cumulative component of connective tissue. Among them, the changes in ion channel gene expression caused by genetic factors are common, which is mainly reported in foreign documents. For example, the mutations of HCN4, SCN5A, etc. However, the progress in biological pacemaker is not ideal as expected, which suggests that there are a lot of new sick sinus syndrome-related genes remain to be discovered. Therefore, the genetic research in sick sinus syndrome will contribute to reveal the pathogenesis of sinus node dysfunction and provide the basis for effective treatment of and biological pacemaker study. Our study systematically explore the role of A-kinase anchoring protein AKAP10in the pathogenesis of sick sinus syndrome, and also analyze its molecular mechanism, with the methods of molecular biology, cell biology, and genetics. Our main findings are:
1. Genetic associaton study of AKAP10with sinus node dysfunction in Han Chinese population
Sick sinus syndrome accounts for more than a half of the implantable cardiac pacemaker surgery, however, the mechanisms of sick sinus syndrome is still unclear. We determined based on a large number of documents retrieved arrhythmia with four closely related genes (AKAP10, Kcnj8, Cacnald, MIR-1) as candidate genes using the PCR-SSCP and direct sequencing methods and finaly determined several SNPs of AKAP10are associated with sinus arrest Firsly we collected456cases with sick sinus syndrome (which including227patients with sinus arrest) and467control. By PCR-SSCP and direct sequencing, we two novel AKAP10mutations:c.682_687delAGAACT (p. Arg228_Thr229de1) in exon4and c.1062-2A> G in intron6. And we also found two SNPs (rs203462and rs4925060) are both significantly correlated with sinus node dysfunction. In summary, we for the first time found two novel AKAP10mutations and two SNPs in sinus node dysfunction patients, which indicates that the AKAP10gene may be involved in the mechanism of sinus node dysfunction, especially in the occurrence of sinus arrest.
The first study found that in patients with sinus arrest AKAP10multiple sites (which contains two new mutations and two SNP loci) change, suggesting that this gene may be involved in AKAP10sick sinus syndrome, especially occurrence of sinus arrest development.
2. The Mechanism of novel mutations of AKAP10associated with sinus node dysfuntion
We constructed the micro gene of AKAP10to prove that the novel mutation c.1062-2A> G in intron6of AKAP10can lead to abnormal RNA splicing, resulting in missing exon7, which may be the possible mechanism of sinus node dysfunction. We detected the transcrips of AKAP10in different human cell lines, including human umbilical vein endothelial cells (HUVEC), human aortic smooth muscle cells (HASMC), human monocytic cell line (THP-1) and myocardial samples from several patients. We found different transcripts of AKAP10in different cell lines (containing exon7or missing exon7),but in the myocardium we found only one transcript of AKAP10(containing exon7), which indicate that the lack of exon7in AKAP10may lead to sick sinus syndrome, and different transcripts of AKAP10may vary in function.
To prove the novel mutation c.682_687delAGAACT (p. Arg228_Thr229de1) in exon4of AKAP10can lead to sinus node dysfunction, we established the earlier (3dpf) zebrafish electrocardiogram detection platform, by injected the RNA to overpressed p. Arg228_Thr229del and then successfully simulated the sinus arrest-like phenotype. We further overexpressed p. Arg228_Thr229del and HCN4/HCN2in HEK293A, and then using the confocol microscopy scaning. Finally we found that compared to the wild type group, the mutant group (p. Arg228_Thr229del) can reduced the expression of HCN4in membrane, which may be the mechanism of occurrence of sinus node dysfunction.
Takern together, by genetic and functional study on AKAP10, we found its essenpial role in regulating the expression of HCN4in membrane, suggesting that AKAP10is possibly involved in the pathogenesis of sinus node dysfunction. The new discoveries would refresh our knowledge in the occurrence and development of sinus node dysfunction and provided new theoretical
Comprehensive two-part research, we adopted the A-type kinase anchoring protein AKAP10investigate genetic and functional analysis, first found its role in regulating the expression of HCN4membrane, suggesting that AKAP10possibly through a mechanism involved in the sinoatrial node cells HCN4trafficking process. The results deepen our understanding of the pathogenesis of diseases associated with sick sinus syndrome, and for the clinical diagnosis and treatment of sick sinus syndrome provides a new theoretical basis for clinical diagnosis and treatment.
引文
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