Bersell, KR;
Yang, T;
Mosley, JD;
Glazer, AM;
Hale, AT;
Kryshtal, DO;
Kim, K;
Steimle, JD;
Brown, JD;
Salem, J-E;
et al.
Bersell, KR; Yang, T; Mosley, JD; Glazer, AM; Hale, AT; Kryshtal, DO; Kim, K; Steimle, JD; Brown, JD; Salem, J-E; Campbell, CC; Hong, CC; Wells, QS; Johnson, AN; Short, L; Blair, MA; Behr, ER; Petropoulou, E; Jamshidi, Y; Benson, MD; Keyes, MJ; Ngo, D; Vasan, RS; Yang, Q; Gerszten, RE; Shaffer, C; Parikh, S; Sheng, Q; Kannankeril, PJ; Moskowitz, IP; York, JD; Wang, TJ; Knollmann, BC; Roden, DM
(2023)
Transcriptional Dysregulation Underlies Both Monogenic Arrhythmia Syndrome and Common Modifiers of Cardiac Repolarization.
Circulation, 147 (10).
pp. 824-840.
ISSN 1524-4539
https://doi.org/10.1161/CIRCULATIONAHA.122.062193
SGUL Authors: Behr, Elijah Raphael Jamshidi, Yalda
![[img]](https://openaccess.sgul.ac.uk/115088/6.hassmallThumbnailVersion/manuscript%20with%208%20figures.pdf) ![](https://openaccess.sgul.ac.uk/115088/6.haspreviewThumbnailVersion/manuscript%20with%208%20figures.pdf) Preview |
|
PDF
Accepted Version
Available under License ["licenses_description_publisher" not defined].
Download (12MB)
| Preview
|
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 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 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). 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.
Item Type: |
Article
|
Additional Information: |
This is a non-final version of an article published in final form in Bersell, KR; Yang, T; Mosley, JD; Glazer, AM; Hale, AT; Kryshtal, DO; Kim, K; Steimle, JD; Brown, JD; Salem, J-E; et al. (2023) Transcriptional Dysregulation Underlies Both Monogenic Arrhythmia Syndrome and Common Modifiers of Cardiac Repolarization. Circulation, 147 (10). pp. 824-840. |
Keywords: |
Brugada syndrome, arrhythmia, genetics, stem cells, arrhythmia, Brugada syndrome, genetics, stem cells, 1102 Cardiorespiratory Medicine and Haematology, 1103 Clinical Sciences, 1117 Public Health and Health Services, Cardiovascular System & Hematology |
SGUL Research Institute / Research Centre: |
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) |
Journal or Publication Title: |
Circulation |
ISSN: |
1524-4539 |
Language: |
eng |
Dates: |
Date | Event |
---|
7 March 2023 | Published | 16 December 2022 | Published Online | 3 November 2022 | Accepted |
|
Publisher License: |
Publisher's own licence |
Projects: |
|
PubMed ID: |
36524479 |
![](http://static.pubmed.gov/portal/portal3rc.fcgi/2745237/img/27842) |
Go to PubMed abstract |
URI: |
https://openaccess.sgul.ac.uk/id/eprint/115088 |
Publisher's version: |
https://doi.org/10.1161/CIRCULATIONAHA.122.062193 |
Statistics
Item downloaded times since 03 Jan 2023.
Actions (login required)
![Edit Item](/style/images/action_view.png) |
Edit Item |