Project Details
Projekt
Hereditary sick sinus syndrome – phenotypic spectrum, genetic basis, cellular dysfunction and implications for therapy
Subject Area
Cardiology, Angiology
Anatomy and Physiology
Anatomy and Physiology
Term
from 2018 to 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 398004441
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.
DFG Programme
Research Grants
Cooperation Partners
Professor Dr. Andreas Draguhn; Professor Dr. Benjamin Meder
