Transcriptional Dysregulation Underlies Both Monogenic Arrhythmia Syndrome and Common Modifiers of Cardiac Repolarization. Issue 10 (16th December 2022)

• Record Type: Journal Article
• Authors: Bersell, Kevin R.; Yang, Tao; Mosley, Jonathan D.; Glazer, Andrew M.; Hale, Andrew T.; Kryshtal, Dmytro O.; Kim, Kyungsoo; Steimle, Jeffrey D.; Brown, Jonathan D.; Salem, Joe-Elie; Campbell, Courtney C.; Hong, Charles C.; Wells, Quinn S.; Johnson, Amanda N.; Short, Laura; Blair, Marcia A.; Behr, Elijah R.; Petropoulou, Evmorfia; Jamshidi, Yalda; Benson, Mark D.; Keyes, Michelle J.; Ngo, Debby; Vasan, Ramachandran S.; Yang, Qiong; Gerszten, Robert E.; Shaffer, Christian; Parikh, Shan; Sheng, Quanhu; Kannankeril, Prince J.; Moskowitz, Ivan P.; York, John D.; Wang, Thomas J.; Knollmann, Bjorn C.; Roden, Dan M.;
• Is Part Of: Circulation. Volume 147:Issue 10(2023)
• Page Start: 824
• Page End: 840
• Publication Date: 2022-12-16
• Subjects: Brugada syndrome -- stem cells -- arrhythmia -- genetics; Blood -- Circulation -- Periodicals; Cardiovascular system -- Periodicals; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; 616.1
• DOI: 10.1161/CIRCULATIONAHA.122.062193
• Languages: English
• ISSNs: 0009-7322

Abstract

Abstract : Background: 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. 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: TBX5-G145R reduced transcriptional activity and caused multiple electrophysiologic abnormalities, including decreased peak and enhanced "late" cardiac sodium current (INa ), 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 INa, and that reduced PDGF receptor ( PDGFRA [platelet-derived growth factor receptor α]) expression and blunted signal transduction to PI3K was implicated in enhanced late INa . Tbx5 regulation of the PDGF axis increased arrhythmia risk due to disruption of PDGF signaling and was conserved in murine model systems. 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). Conclusions: 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.