Transcriptional Dysregulation Underlies Both Monogenic Arrhythmia Syndrome and Common Modifiers of Cardiac Repolarization


 
 
 Brugada syndrome (BrS) is an inherited arrhythmia syndrome caused by loss-of-function variants in the cardiac sodium channel gene
 SCN5A
 (sodium voltage-gated channel alpha subunit 5) in ≈20% of subjects. We identified a family with 4 individuals diagnosed with BrS harboring the rare G145R missense variant in the cardiac transcription factor
 TBX5
 (T-box transcription factor 5) and no
 SCN5A
 variant.
 
 
 
 
 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 corrected QT (QTc) interval association with serum PDGF was tested in the Framingham Heart Study cohort (n=1893 individuals).
 
 
 
 
 TBX5-G145R reduced transcriptional activity and caused multiple electrophysiologic abnormalities, including decreased peak and enhanced “late” cardiac sodium current (I
 Na
 ), which were entirely corrected by editing G145R to wild-type. Transcriptional profiling and functional assays in genome-unedited and -edited iPSC-CMs showed direct
 SCN5A
 down-regulation caused decreased peak I
 Na
 , and that reduced PDGF receptor (
 PDGFRA
 [platelet-derived growth factor receptor α]) expression and blunted signal transduction to PI3K was implicated in enhanced late I
 Na
 . Tbx5 regulation of the PDGF axis and disruption of PDGF signaling, which causes arrhythmia risk, were both conserved in murine model systems. The PDGF receptor blockade markedly prolonged normal iPSC-CM action potentials and plasma levels of PDGF in the Framingham Heart Study were inversely correlated with the QTc interval (
 P
 <0.001).
 
 
 
 
 
 These results not only establish decreased
 SCN5A
 transcription by the
 TBX5
 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.
 
