FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4313281258> ?p ?o ?g. }

• W4313281258 endingPage "840" @default.
• W4313281258 startingPage "824" @default.
• W4313281258 abstract "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 rate-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 (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).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." @default.
• W4313281258 created "2023-01-06" @default.
• W4313281258 creator A5000717517 @default.
• W4313281258 creator A5001971319 @default.
• W4313281258 creator A5004294653 @default.
• W4313281258 creator A5004656494 @default.
• W4313281258 creator A5004784080 @default.
• W4313281258 creator A5005710964 @default.
• W4313281258 creator A5009328116 @default.
• W4313281258 creator A5011046385 @default.
• W4313281258 creator A5014595045 @default.
• W4313281258 creator A5020143572 @default.
• W4313281258 creator A5025524446 @default.
• W4313281258 creator A5028918247 @default.
• W4313281258 creator A5029187572 @default.
• W4313281258 creator A5037310566 @default.
• W4313281258 creator A5040171040 @default.
• W4313281258 creator A5047862162 @default.
• W4313281258 creator A5049939460 @default.
• W4313281258 creator A5053093055 @default.
• W4313281258 creator A5053271274 @default.
• W4313281258 creator A5054368544 @default.
• W4313281258 creator A5058141203 @default.
• W4313281258 creator A5061410829 @default.
• W4313281258 creator A5063087770 @default.
• W4313281258 creator A5064477997 @default.
• W4313281258 creator A5064815370 @default.
• W4313281258 creator A5065502559 @default.
• W4313281258 creator A5068844010 @default.
• W4313281258 creator A5076059643 @default.
• W4313281258 creator A5080126593 @default.
• W4313281258 creator A5085451281 @default.
• W4313281258 creator A5086895898 @default.
• W4313281258 creator A5087728526 @default.
• W4313281258 creator A5088893226 @default.
• W4313281258 creator A5091110504 @default.
• W4313281258 date "2023-03-07" @default.
• W4313281258 modified "2023-10-17" @default.
• W4313281258 title "Transcriptional Dysregulation Underlies Both Monogenic Arrhythmia Syndrome and Common Modifiers of Cardiac Repolarization" @default.
• W4313281258 cites W1491803208 @default.
• W4313281258 cites W1540071197 @default.
• W4313281258 cites W1969629906 @default.
• W4313281258 cites W1970162068 @default.
• W4313281258 cites W1971343049 @default.
• W4313281258 cites W1971694756 @default.
• W4313281258 cites W1973431915 @default.
• W4313281258 cites W1977709885 @default.
• W4313281258 cites W1979420087 @default.
• W4313281258 cites W1983015524 @default.
• W4313281258 cites W1989950796 @default.
• W4313281258 cites W1994107787 @default.
• W4313281258 cites W1997956247 @default.
• W4313281258 cites W2000081470 @default.
• W4313281258 cites W2002754883 @default.
• W4313281258 cites W2005221088 @default.
• W4313281258 cites W2005675562 @default.
• W4313281258 cites W2010638459 @default.
• W4313281258 cites W2018514939 @default.
• W4313281258 cites W2024695712 @default.
• W4313281258 cites W2030097304 @default.
• W4313281258 cites W2041100469 @default.
• W4313281258 cites W2041652776 @default.
• W4313281258 cites W2043655170 @default.
• W4313281258 cites W2044873676 @default.
• W4313281258 cites W2048811598 @default.
• W4313281258 cites W2067267790 @default.
• W4313281258 cites W2071172093 @default.
• W4313281258 cites W2074093573 @default.
• W4313281258 cites W2078311582 @default.
• W4313281258 cites W2082711051 @default.
• W4313281258 cites W2084373725 @default.
• W4313281258 cites W2089861793 @default.
• W4313281258 cites W2095569622 @default.
• W4313281258 cites W2098405483 @default.
• W4313281258 cites W2099883675 @default.
• W4313281258 cites W2099970347 @default.
• W4313281258 cites W2100604934 @default.
• W4313281258 cites W2102552083 @default.
• W4313281258 cites W2104184627 @default.
• W4313281258 cites W2110884637 @default.
• W4313281258 cites W2111338617 @default.
• W4313281258 cites W2112958592 @default.
• W4313281258 cites W2113693040 @default.
• W4313281258 cites W2114104545 @default.
• W4313281258 cites W2117619772 @default.
• W4313281258 cites W2122506519 @default.
• W4313281258 cites W2131237335 @default.
• W4313281258 cites W2132119243 @default.
• W4313281258 cites W2132572082 @default.
• W4313281258 cites W2137802443 @default.
• W4313281258 cites W2138207763 @default.
• W4313281258 cites W2139639233 @default.
• W4313281258 cites W2140729960 @default.
• W4313281258 cites W2141905395 @default.
• W4313281258 cites W2142550975 @default.
• W4313281258 cites W2146512944 @default.
• W4313281258 cites W2147678422 @default.
• W4313281258 cites W2147841875 @default.

• next