Hereditary sick sinus syndrome – phenotypic spectrum, genetic basis, cellular dysfunction and implications for therapy

遗传性病态窦房结综合征 â 表型谱、遗传基础、细胞功能障碍和治疗意义

• 批准号: 398004441
• 负责人: Professor Dr. Patrick A. Schweizer
• 金额: --
• 依托单位: Abteilung Neuro- und Sinnesphysiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/398004441?language=en
• 关键词: Hereditary; sick; sinus; syndrome; phenotypic

Sick sinus syndrome (SSS) is a frequent clinical entity with significant morbidity and mortality, which is a major indication for the implantation of electronic pacemakers. However, the pathogenetic mechanisms underlying SSS are incompletely understood. Furthermore, current assessment and therapeutic decision making of SSS patients is largely based on clinical symptoms and does not consider mechanism-based aspects. We and others demonstrated that SSS at least in parts originates from distinct genetic defects and/or predisposing genetic constellations, but a comprehensive assessment of mechanisms underlying hereditary SSS is not available to date. Given the broad phenotypic spectrum of familial SSS including overlapping arrhythmia syndromes and structural cardiac abnormalities, we hypothesize that specified genetic defects are key to distinct clinical profiles. We have established a large cohort of clinically well-defined patients with primary SSS. In a preparatory candidate gene approach we have identified novel mutations in the pacemaker gene HCN4, which will be subjected to in-depth functional characterization using an in vitro SSS disease model on the basis of our recently developed approach to specifically generate human iPSC-derived pacemaker cells. In a next step we will perform RNA sequencing to delineate pathways importantly implicated in the cellular differentiation of iPSC-derived pacemaker cells to unveil novel, yet unknown pacemaker relevant targets and potential mechanisms for SSS. Comparative transcriptome analysis with pacemaker cells carrying the identified pathogenic HCN4 mutations will provide novel insight into HCN4-related transcriptional networks. To identify potentially novel SSS mutations and disease genes within our patient registry we will apply next-generation and whole exome sequencing. Identified mutations will be characterized at molecular and electrophysiological levels. Our goal is to establish a comprehensive classification of hereditary SSS for future, individualized clinical assessment based on mechanism-specific disease profiles.

病态窦房结综合征(SSS)是一种常见的临床实体，其发病率和死亡率都很高，这是植入电子起搏器的主要适应症。然而，SSS的发病机制尚不完全清楚。此外，目前对SSS患者的评估和治疗决策主要是基于临床症状，而没有考虑基于机制的方面。我们和其他人证明了SSS至少部分起源于不同的遗传缺陷和/或易感的遗传星座，但到目前为止还没有对遗传性SSS潜在机制的全面评估。考虑到家族性SSs的广泛表型谱，包括重叠的心律失常综合征和结构性心脏异常，我们假设特定的基因缺陷是不同临床特征的关键。我们已经建立了大量临床明确的原发性SSS患者队列。在一种预备候选基因方法中，我们已经确定了起搏器基因HCN4的新突变，在我们最近开发的特异性产生人IPSC来源的起搏细胞的方法的基础上，将使用体外SSS疾病模型对其进行深入的功能表征。在下一步，我们将进行RNA测序，以描绘在IPSC来源的起搏细胞的细胞分化中重要的途径，以揭示SSS的新的、尚不清楚的起搏器相关靶点和潜在机制。对携带已识别的致病HCN4突变的起搏细胞进行的比较转录组分析将为了解与HCN4相关的转录网络提供新的见解。为了在我们的患者登记中识别潜在的新的SSS突变和疾病基因，我们将应用下一代和整个外显子组测序。已确定的突变将在分子和电生理水平上进行表征。我们的目标是建立一个遗传性SS的全面分类，用于未来基于特定机制的疾病特征的个体化临床评估。