The TBX5-G145R variant causes Brugada syndrome and reveals a transcriptional mechanism of arrhythmogenesis involving enhanced late sodium current due to reduced PDGF receptor-mediated PI3K signaling.
Does the TBX5-G145R variant cause Brugada syndrome through transcriptional dysregulation of the PDGF/PI3K pathway?
The TBX5-G145R variant causes Brugada syndrome via a novel transcriptional mechanism involving reduced PDGF receptor-mediated PI3K signaling, which enhances late sodium current.
p-value: p=<0.001
BACKGROUND: variant. METHODS: We generated induced pluripotent stem cells (iPSCs) from 2 members of a family carrying TBX5-G145R and diagnosed with Brugada syndrome. After differentiation to iPSC-derived cardiomyocytes (iPSC-CMs), electrophysiologic characteristics were assessed by voltage- and current-clamp experiments (n=9 to 21 cells per group) and transcriptional differences by RNA sequencing (n=3 samples per group), and compared with iPSC-CMs in which G145R was corrected by CRISPR/Cas9 approaches. The role of platelet-derived growth factor (PDGF)/phosphoinositide 3-kinase (PI3K) pathway was elucidated by small molecule perturbation. The rate-corrected QT (QTc) interval association with serum PDGF was tested in the Framingham Heart Study cohort (n=1893 individuals). RESULTS: <0.001). CONCLUSIONS: variant as a cause of BrS, but also reveal a new general transcriptional mechanism of arrhythmogenesis of enhanced late sodium current caused by reduced PDGF receptor-mediated PI3K signaling.
Bersell et al. (Fri,) conducted a other in Brugada syndrome (n=1,893). TBX5-G145R mutation vs. CRISPR/Cas9 corrected iPSC-CMs was evaluated on Electrophysiologic characteristics, transcriptional differences, and QTc interval association with serum PDGF (p=<0.001). The TBX5-G145R variant causes Brugada syndrome and reveals a transcriptional mechanism of arrhythmogenesis involving enhanced late sodium current due to reduced PDGF receptor-mediated PI3K signaling.