Myotonic dystrophy type 1 (DM1) is a multisystemic genetic disorder caused by the CTG repeat expansion in the 3'-untranslated region of DMPK gene. Heart dysfunctions occur in ∼80% of DM1 patients and are the second leading cause of DM1-related deaths. Herein, we report that upregulation of a non-muscle splice isoform of RNA-binding protein RBFOX2 in DM1 heart tissue-due to altered splicing factor and microRNA activities-induces cardiac conduction defects in DM1 individuals. Mice engineered to express the non-muscle RBFOX240 isoform in heart via tetracycline-inducible transgenesis, or CRISPR/Cas9-mediated genome editing, reproduced DM1-related cardiac conduction delay and spontaneous episodes of arrhythmia. Further, by integrating RNA binding with cardiac transcriptome datasets from DM1 patients and mice expressing the non-muscle RBFOX2 isoform, we identified RBFOX240-driven splicing defects in voltage-gated sodium and potassium channels, which alter their electrophysiological properties. Thus, our results uncover a trans-dominant role for an aberrantly expressed RBFOX240 isoform in DM1 cardiac pathogenesis.

中文翻译：

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非肌肉 RBFOX2 亚型的异常表达会引发强直性肌营养不良中的心脏传导缺陷。

强直性肌营养不良 1 型 (DM1) 是一种多系统遗传性疾病，由 DMPK 基因 3'-非翻译区 CTG 重复扩增引起。大约 80% 的 DM1 患者会出现心功能障碍，这是 DM1 相关死亡的第二大原因。在此，我们报告了 DM1 心脏组织中 RNA 结合蛋白 RBFOX2 的非肌肉剪接亚型的上调（由于剪接因子和 microRNA 活性的改变）导致 DM1 个体的心脏传导缺陷。通过四环素诱导转基因或 CRISPR/Cas9 介导的基因组编辑，小鼠被改造为在心脏中表达非肌肉 RBFOX240 亚型，再现了 DM1 相关的心脏传导延迟和自发性心律失常发作。此外，通过将 RNA 结合与来自 DM1 患者和表达非肌肉 RBFOX2 亚型的小鼠的心脏转录组数据集整合，我们发现了电压门控钠和钾通道中 RBFOX240 驱动的剪接缺陷，这改变了它们的电生理特性。因此，我们的结果揭示了异常表达的 RBFOX240 亚型在 DM1 心脏发病机制中的反式显性作用。