当前位置: X-MOL 学术Circulation › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Transcriptional Dysregulation Underlies Both Monogenic Arrhythmia Syndrome and Common Modifiers of Cardiac Repolarization
Circulation ( IF 37.8 ) Pub Date : 2022-12-16 , DOI: 10.1161/circulationaha.122.062193
Kevin R Bersell 1 , Tao Yang 2 , Jonathan D Mosley 1 , Andrew M Glazer 1 , Andrew T Hale 3 , Dmytro O Kryshtal 1 , Kyungsoo Kim 1 , Jeffrey D Steimle 4 , Jonathan D Brown 2 , Joe-Elie Salem 1, 2, 5, 6 , Courtney C Campbell 1 , Charles C Hong 7 , Quinn S Wells 1, 2, 8 , Amanda N Johnson 9 , Laura Short 2 , Marcia A Blair 2 , Elijah R Behr , Evmorfia Petropoulou 10 , Yalda Jamshidi 10 , Mark D Benson 11, 12 , Michelle J Keyes 11 , Debby Ngo 13 , Ramachandran S Vasan 14 , Qiong Yang 14 , Robert E Gerszten 11, 13 , Christian Shaffer 2 , Shan Parikh 1 , Quanhu Sheng , Prince J Kannankeril 15 , Ivan P Moskowitz 4 , John D York 3 , Thomas J Wang 2 , Bjorn C Knollmann 1, 2 , Dan M Roden 1, 2, 8
Affiliation  

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.

中文翻译:

转录失调是单基因心律失常综合征和心脏复极化常见修饰因子的基础

背景:Brugada 综合征 (BrS) 是一种遗传性心律失常综合征,由约 20% 的受试者的心脏钠通道基因SCN5A(钠电压门控通道 α 亚基 5)功能丧失变异引起。我们确定了一个家庭,有 4 名被诊断患有 BrS 的人携带心脏转录因子TBX5(T-box 转录因子 5)中罕见的 G145R 错义变异并且没有SCN5A方法:我们从携带 TBX5-G145R 并被诊断患有 Brugada 综合征的 2 名家庭成员中生成诱导多能干细胞 (iPSC)。在分化为 iPSC 衍生的心肌细胞 (iPSC-CM) 后,通过电压和电流钳实验(每组 n=9 至 21 个细胞)评估电生理特征,并通过 RNA 测序评估转录差异(每组 n=3 个样本),并与通过 CRISPR/Cas9 方法校正 G145R 的 iPSC-CM 进行比较。血小板衍生生长因子 (PDGF)/磷酸肌醇 3 激酶 (PI3K) 通路的作用通过小分子微扰得到阐明。在 Framingham 心脏研究队列(n=1893 人)中测试了校正后的 QT (QTc) 间期与血清 PDGF 的关联。 结果:Na),通过将 G145R 编辑为野生型来完全纠正。基因组未经编辑和编辑的 iPSC-CM 中的转录谱分析和功能测定显示直接SCN5A下调导致峰值 I Na降低,并且 PDGF 受体(PDGFRA [血小板衍生生长因子受体 α])表达和信号转导减弱PI3K 与增强晚期 I Na有关。导致心律失常风险的 PDGF 轴的 Tbx5 调节和 PDGF 信号传导的破坏在小鼠模型系统中均被保守。PDGF 受体阻断显着延长了正常的 iPSC-CM 动作电位,Framingham 心脏研究中 PDGF 的血浆水平与 QTc 间期呈负相关(P<0.001). 结论:这些结果不仅确定了TBX5变体的SCN5A转录减少是 BrS 的原因,而且还揭示了由 PDGF 受体介导的 PI3K 信号传导减少引起的晚期钠电流增强的心律失常发生的新的一般转录机制。
更新日期:2022-12-16
down
wechat
bug