进行性家族性心脏传导阻滞II型致病基因鉴定和机制研究

Progressive familial heart block (PFHB) is a progressive cardiac conduction disorder, which includes type I and type II. PFHB type II is manifested as atrioventricular node disease, accompanied with atrioventricular block and an idionodal escape rhythm, which is progressive. When complete heart block with narrow QRS complexes supervenes, syncopal episodes or sudden deaths often occur and the Pacemaker implantation is recommended for treatment. Some variants in the genes encoding ion channel, cardiac connexins and transcription factors have been reported to be associated with PFHB type I. However, the pathogenic gene for PFHB type II has not been identified. In the preliminary study, we have identified the insulin-like growth factor-binding protein 5 gene (IGFBP5) as a possible disease-causing gene for PFHB type II in a Han Chinese family, and the hypothesis that the IGFBP5 gene mutation may lead to PFHB type II by changing calcium currents in a dominant-negative effect was proposed. This project will further confirm the relationship between the IGFBP5 gene and PFHB type II, and identify the mutation frequency in PFHB type II patients. New pathogenic genes and mutations for PFHB type II will be identified by exome sequencing and whole genome sequencing. By constructing expression plasmids with the specific gene mutation, function and transcriptome sequencing analyses will be performed to explore the pathogenesis of gene mutations for PFHB type II.

进行性家族性心脏传导阻滞(PFHB)是一种进行性心脏传导疾病，包括I型和II型。其中II型表现为房室结疾病伴房室传导阻滞和结性逸搏心律，呈进行性加重。当疾病发展至完全性心脏传导阻滞并伴窄QRS波群发作时，常引起晕厥或猝死，需植入起搏器治疗。已报道编码离子通道、心脏连接蛋白和转录因子基因变异与PFHB I型相关，但仍未鉴定PFHB II型致病基因。我们前期研究发现胰岛素样生长因子结合蛋白5基因(IGFBP5)可能是一个中国汉族PFHB II型家系的致病基因，提出“IGFBP5基因突变可能通过显性负性效应引起钙离子电流改变导致PFHB II型”这一假设。本项目拟进一步验证IGFBP5基因与PFHB II型的关系并鉴定PFHB II型患者的突变频率，通过外显子组测序和全基因组测序鉴定PFHB II型新致病基因和突变，构建基因突变表达质粒开展功能分析和转录组测序等，探讨基因突变导致疾病发生的机制。

进行性家族性心脏传导阻滞(progressive familial heart block, PFHB)是一种进行性心脏传导疾病，包括I型和II型。其中II型表现为房室结疾病伴房室传导阻滞和结性逸搏心律，呈进行性加重。当疾病发展至完全性心脏传导阻滞并伴窄QRS波群发作时，常引起晕厥或猝死，需植入起搏器治疗。已报道编码离子通道、心脏连接蛋白和转录因子的基因变异与PFHB I型相关，但仍未鉴定PFHB II型致病基因。我们前期研究发现胰岛素样生长因子结合蛋白5基因（the insulin-like growth factor-binding protein 5 gene，IGFBP5）可能是一个中国汉族PFHB II型家系的致病基因，c.239G>T（p.C80F）杂合变异与该家系疾病表型共分离，可能是其致病基因突变。本研究进一步明确了IGFBP5基因变异在心脏传导疾病中的发生频率，应用全外显子组测序等对一些家系进一步分析，筛选鉴定了3个家系的基因变异。通过构建疾病基因野生型和突变表达质粒，运用细胞培养、转染、蛋白表达、细胞周期、细胞迁移、免疫共沉淀和质谱等分析方法，进一步探讨了IGFBP5基因c.239G>T（p.C80F）突变导致心脏传导阻滞发生的可能机制。

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