ArticleCirculation2023
Transcriptional Dysregulation Underlies Both Monogenic Arrhythmia Syndrome and Common Modifiers of Cardiac Repolarization.
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Article in Circulation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20citing papers in PubMed
3.8field-weighted citation impact, top 5% of its field
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20 citing papers in PubMed, 26 citations in OpenAlex.
- Automated patch clamp data improve variant classification and penetrance stratification for SCN5A-Brugada syndrome.European heart journal · 2026Article
- Entrectinib results in ventricular tachycardia and Brugada phenocopy through inhibition of sodium current.Cardio-oncology (London, England) · 2026Article
- Human iPSCs: atrial versus ventricular cardiomyocytes and their functional and pharmacological differences.Biochemical Society transactions · 2026Review
- Reduced TBX5 dosage undermines developmental control of atrial cardiomyocyte identity in a model of human atrial disease.Development (Cambridge, England) · 2026Article
- A new approach methodology for studying intrinsic ventricular arrhythmias in Fabry disease.Frontiers in cardiovascular medicine · 2026Article
- Molecular pathways, tissue-specific roles, and therapeutic opportunities in mitochondrial resilience-based strategies for insulin resistance.Frontiers in clinical diabetes and healthcare · 2026Review
- The role of iPSC research for insight into inherited arrhythmia conditions.Heart rhythm · 2025Review
- Atypical Holt-Oram syndrome: Early-onset sick sinus syndrome in a Japanese family with a novelJournal of cardiology cases · 2025Article
- Abnormal CaFrontiers in pharmacology · 2025Article
- Epicardial Ablation for Arrhythmogenic Disorders in Patients with Brugada Syndrome.Biomedicines · 2024Review
- Single-nuclei transcriptomics reveals TBX5-dependent targets in a patient with Holt-Oram syndrome.The Journal of clinical investigation · 2024Article
- ParSE-seq: a calibrated multiplexed assay to facilitate the clinical classification of putative splice-altering variants.Nature communications · 2024Article
- Lessons on the non-linear path of medical progress and biological complexity from mouse models of the Brugada syndrome.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2024Article
- Top stories on the study of inherited arrhythmias using iPSCs.Heart rhythm · 2024Review
- Stem cell models of inherited arrhythmias.Nature cardiovascular research · 2024Review
- Advances in understanding of cardiac sodium channel structure/function and their relation to disease pathogenesis and treatment.Heart rhythm · 2024Article
- Brugada Syndrome: More than a Monogenic Channelopathy.Biomedicines · 2023Review
- Multicenter clinical and functional evidence reclassifies a recurrent noncanonical filamin C splice-altering variant.Heart rhythm · 2023Article
- Loss of PI3Kα Mediates Protection From Myocardial Ischemia-Reperfusion Injury Linked to Preserved Mitochondrial Function.Journal of the American Heart Association · 2023Article
- Automated Patch-Clamp and Induced Pluripotent Stem Cell-Derived Cardiomyocytes: A Synergistic Approach in the Study of Brugada Syndrome.International journal of molecular sciences · 2023Review
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Authors and funding
34 authors at 9 institutions in 6 countries.
Kevin R BersellDepartments of Pharmacology (K.R.B., A.M.G., D.O.K., K.K., J-E.S., C.C.C., Q.S.W., S.P., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN.ORCID 0000-0002-3176-4519
Tao YangMedicine (T.Y., J.D.M., J.D.B., J-E.S., Q.S.W., L.S., M.A.B., C.S., T.J.W., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN.
Jonathan D MosleyDepartments of Pharmacology (K.R.B., A.M.G., D.O.K., K.K., J-E.S., C.C.C., Q.S.W., S.P., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN.ORCID 0000-0001-6421-2887
Andrew M GlazerDepartments of Pharmacology (K.R.B., A.M.G., D.O.K., K.K., J-E.S., C.C.C., Q.S.W., S.P., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN.ORCID 0000-0002-3938-4713
Andrew T HaleBiochemistry (A.T.H., J.D.Y.), Vanderbilt University, Nashville, TN.
Dmytro O KryshtalDepartments of Pharmacology (K.R.B., A.M.G., D.O.K., K.K., J-E.S., C.C.C., Q.S.W., S.P., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN.ORCID 0000-0002-0427-6587
Kyungsoo KimDepartments of Pharmacology (K.R.B., A.M.G., D.O.K., K.K., J-E.S., C.C.C., Q.S.W., S.P., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN.ORCID 0000-0003-2869-0659
Jeffrey D SteimleDepartments of Pediatrics, Pathology, and Human Genetics, University of Chicago, IL (J.D.S., I.P.M.).
Jonathan D BrownMedicine (T.Y., J.D.M., J.D.B., J-E.S., Q.S.W., L.S., M.A.B., C.S., T.J.W., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN.ORCID 0000-0002-0359-6167
Joe-Elie SalemDepartments of Pharmacology (K.R.B., A.M.G., D.O.K., K.K., J-E.S., C.C.C., Q.S.W., S.P., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN.ORCID 0000-0002-0331-3307
Courtney C CampbellDepartments of Pharmacology (K.R.B., A.M.G., D.O.K., K.K., J-E.S., C.C.C., Q.S.W., S.P., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN.
Charles C HongDepartment of Medicine, University of Maryland School of Medicine, Baltimore (C.C.H.).ORCID 0000-0002-0424-8252
Quinn S WellsDepartments of Pharmacology (K.R.B., A.M.G., D.O.K., K.K., J-E.S., C.C.C., Q.S.W., S.P., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN.ORCID 0000-0003-3899-0313
Amanda N JohnsonMolecular Physiology and Biophysics (A.N.J.), Vanderbilt University, Nashville, TN.ORCID 0000-0001-7594-6747
Laura ShortMedicine (T.Y., J.D.M., J.D.B., J-E.S., Q.S.W., L.S., M.A.B., C.S., T.J.W., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN.
Marcia A BlairMedicine (T.Y., J.D.M., J.D.B., J-E.S., Q.S.W., L.S., M.A.B., C.S., T.J.W., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN.
Elijah R BehrORCID 0000-0002-8731-2853
Evmorfia PetropoulouCardiology Clinical Academic Group, Molecular and Clinical Sciences Institute, St George's, University of London and St George's University Hospitals National Health Service Foundation Trust, London, UK (E.P., Y.J.).
Yalda JamshidiCardiology Clinical Academic Group, Molecular and Clinical Sciences Institute, St George's, University of London and St George's University Hospitals National Health Service Foundation Trust, London, UK (E.P., Y.J.).ORCID 0000-0003-0151-6482
Mark D BensonCardiovascular Research Center (E.J.B., M.D.B., M.J.K., R.E.G.), Beth Israel Deaconess Hospital, Boston, MA.
Michelle J KeyesCardiovascular Research Center (E.J.B., M.D.B., M.J.K., R.E.G.), Beth Israel Deaconess Hospital, Boston, MA.ORCID 0000-0003-0303-1390
Debby NgoDivision of Pulmonary and Cardiovascular Medicine (D.N., R.E.G.), Beth Israel Deaconess Hospital, Boston, MA.ORCID 0000-0003-2681-3475
Ramachandran S VasanBoston University School of Medicine, MA (R.S.V., Q.Y.).ORCID 0000-0001-7357-5970
Qiong YangBoston University School of Medicine, MA (R.S.V., Q.Y.).ORCID 0000-0002-3658-1375
Robert E GersztenCardiovascular Research Center (E.J.B., M.D.B., M.J.K., R.E.G.), Beth Israel Deaconess Hospital, Boston, MA.ORCID 0000-0002-6767-7687
Christian ShafferMedicine (T.Y., J.D.M., J.D.B., J-E.S., Q.S.W., L.S., M.A.B., C.S., T.J.W., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN.
Shan ParikhDepartments of Pharmacology (K.R.B., A.M.G., D.O.K., K.K., J-E.S., C.C.C., Q.S.W., S.P., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN.
Quanhu ShengORCID 0000-0001-8951-9295
Prince J KannankerilPediatrics (P.J.K.), Vanderbilt University, Nashville, TN.ORCID 0000-0002-1529-9872
Ivan P MoskowitzDepartments of Pediatrics, Pathology, and Human Genetics, University of Chicago, IL (J.D.S., I.P.M.).ORCID 0000-0003-0014-4963
John D YorkBiochemistry (A.T.H., J.D.Y.), Vanderbilt University, Nashville, TN.
Thomas J WangMedicine (T.Y., J.D.M., J.D.B., J-E.S., Q.S.W., L.S., M.A.B., C.S., T.J.W., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN.ORCID 0000-0003-4063-6508
Bjorn C KnollmannDepartments of Pharmacology (K.R.B., A.M.G., D.O.K., K.K., J-E.S., C.C.C., Q.S.W., S.P., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN.ORCID 0000-0003-4956-9735
Dan M RodenDepartments of Pharmacology (K.R.B., A.M.G., D.O.K., K.K., J-E.S., C.C.C., Q.S.W., S.P., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN.ORCID 0000-0002-6302-0389
Vanderbilt University · USNorwegian Womens Public Health Association · NOBeth Israel Deaconess Medical Center · USBoston University · USSt George’s University Hospitals NHS Foundation Trust · GBUniversity of Chicago · USBrigham and Women's Hospital · USDeaconess Hospital · USUniversity of Maryland, Baltimore · US
Funding
Tumor Immunology and Microenvironment Research ProgramP30CA068485 · NCI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI MATTHEW J TYSKA · 1995 to 2026
$172.8MVANDERBILT UNIVERSITY CTSA FOR PEDIATRIC RESEARCHUL1RR024975 · NCRR · VANDERBILT UNIVERSITY · PI BERNARD, GORDON RAPHAEL · 2007 to 2011
$45.7MMEDICAL SCIENTIST TRAINING PROGRAMT32GM007347 · NIGMS · VANDERBILT UNIVERSITY · PI WILLIAMS, CHRISTOPHER S. · 1985 to 2023
$26.3MMolecular And Cellular Biology Training ProgramT32GM007183 · NIGMS · UNIVERSITY OF CHICAGO · PI GLICK, BENJAMIN S, RICE, PHOEBE A · 1985 to 2021
$23.9MShop Module CoreP30EY008126 · NEI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI Kevin L Schey · 1989 to 2026
$19.6MPharmacogenomics of Arrhythmia TherapyU19HL065962 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI RODEN, DAN M · 2010 to 2014
$17.4MMULTIDISCIPLINARY TRAINING IN MOLECULAR ENDOCRINOLOGYT32DK007563 · NIDDK · VANDERBILT UNIVERSITY · PI Richard M O'Brien · 1988 to 2026
$15.9MUnderstanding and preventing HLA-associated drug reactionsP50GM115305 · NIGMS · VANDERBILT UNIVERSITY MEDICAL CENTER · PI DENNY, JOSHUA C. · 2015 to 2019
$13.0MMULTIDISCIPLINARY CARDIAC SCIENCEST32HL007381 · NHLBI · UNIVERSITY OF CHICAGO · PI JEANNE M DECARA, Yoav Gilad · 1985 to 2026
$12.5MCLINICAL PHARMACOLOGY TRAINING PROGRAMT32GM007569 · NIGMS · VANDERBILT UNIVERSITY MEDICAL CENTER · PI Bjorn C Knollmann · 1985 to 2026
$12.4MVANTAGE:Consolidation to create the Vanderbilt Technologies for Advanced GenomicsG20RR030956 · NCRR · VANDERBILT UNIVERSITY · PI PIETENPOL, JENNIFER A · 2010 to 2010
$8.7MToward a Mechanism-Based Approach to Treating Cardiac ArrhythmiaR35HL144980 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI KNOLLMANN, BJORN C · 2019 to 2025
$7.1MAmerican Heart Association-American Stroke Association 16FTF30130005NCI NIH HHS P30 CA068485NCRR NIH HHS G20 RR030956NCRR NIH HHS UL1 RR024975NEI NIH HHS P30 EY008126NHGRI NIH HHS R00 HG010904NHLBI NIH HHS F30 HL127962NHLBI NIH HHS F30 HL131179NHLBI NIH HHS K08 HL145095NHLBI NIH HHS R01 HL135129NHLBI NIH HHS R01 HL149826NHLBI NIH HHS R35 HL144980NHLBI NIH HHS T32 HL007381NHLBI NIH HHS U19 HL065962NIDDK NIH HHS T32 DK007563NIGMS NIH HHS P50 GM115305NIGMS NIH HHS R01 GM115892NIGMS NIH HHS R01 GM124404NIGMS NIH HHS T32 GM007183NIGMS NIH HHS T32 GM007347NIGMS NIH HHS T32 GM007569NINDS NIH HHS T32 NS007491
Abstract
backgroundBrugada syndrome (BrS) is an inherited arrhythmia syndrome caused by loss-of-function variants in the cardiac sodium channel gene
methodsWe 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).
resultsTBX5-G145R reduced transcriptional activity and caused multiple electrophysiologic abnormalities, including decreased peak and enhanced "late" cardiac sodium current (I
conclusionsThese results not only establish decreased
Indexed as
Brugada SyndromeAnimalsArrhythmias, CardiacHumansMiceMyocytes, CardiacNAV1.5 Voltage-Gated Sodium ChannelPhenotypePhosphatidylinositol 3-KinasesReceptors, Platelet-Derived Growth FactorSodiumNAV1.5 Voltage-Gated Sodium ChannelPhosphatidylinositol 3-KinasesReceptors, Platelet-Derived Growth FactorSodiumarrhythmiaBrugada syndromegeneticsstem cells
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