{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T08:48:25Z","timestamp":1793090905335,"version":"4.5.0"},"reference-count":106,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2023,3,7]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              Brugada syndrome (BrS) is an inherited arrhythmia syndrome caused by loss-of-function variants in the cardiac sodium channel gene\n              <jats:italic>SCN5A<\/jats:italic>\n              (sodium voltage-gated channel alpha subunit 5) in \u224820% of subjects. We identified a family with 4 individuals diagnosed with BrS harboring the rare G145R missense variant in the cardiac transcription factor\n              <jats:italic>TBX5<\/jats:italic>\n              (T-box transcription factor 5) and no\n              <jats:italic>SCN5A<\/jats:italic>\n              variant.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>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).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              TBX5-G145R reduced transcriptional activity and caused multiple electrophysiologic abnormalities, including decreased peak and enhanced \u201clate\u201d cardiac sodium current (I\n              <jats:sub>Na<\/jats:sub>\n              ), which were entirely corrected by editing G145R to wild-type. Transcriptional profiling and functional assays in genome-unedited and -edited iPSC-CMs showed direct\n              <jats:italic>SCN5A<\/jats:italic>\n              down-regulation caused decreased peak I\n              <jats:sub>Na<\/jats:sub>\n              , and that reduced PDGF receptor (\n              <jats:italic>PDGFRA<\/jats:italic>\n              [platelet-derived growth factor receptor \u03b1]) expression and blunted signal transduction to PI3K was implicated in enhanced late I\n              <jats:sub>Na<\/jats:sub>\n              . 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 (\n              <jats:italic>P<\/jats:italic>\n              &lt;0.001).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              These results not only establish decreased\n              <jats:italic>SCN5A<\/jats:italic>\n              transcription by the\n              <jats:italic>TBX5<\/jats:italic>\n              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\u2013mediated PI3K signaling.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.122.062193","type":"journal-article","created":{"date-parts":[[2022,12,16]],"date-time":"2022-12-16T10:00:32Z","timestamp":1671184832000},"page":"824-840","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":27,"title":["Transcriptional Dysregulation Underlies Both Monogenic Arrhythmia Syndrome and Common Modifiers of Cardiac Repolarization"],"prefix":"10.1161","volume":"147","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3176-4519","authenticated-orcid":true,"given":"Kevin R.","family":"Bersell","sequence":"first","affiliation":[{"name":"Departments 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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Yang","sequence":"additional","affiliation":[{"name":"Medicine (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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6421-2887","authenticated-orcid":true,"given":"Jonathan D.","family":"Mosley","sequence":"additional","affiliation":[{"name":"Departments 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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3938-4713","authenticated-orcid":true,"given":"Andrew M.","family":"Glazer","sequence":"additional","affiliation":[{"name":"Departments 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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew T.","family":"Hale","sequence":"additional","affiliation":[{"name":"Biochemistry (A.T.H., J.D.Y.), Vanderbilt University, Nashville, 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