Department of Biochemistry, University of Illinois, Urbana-Champaign, Urbana, IL, USA.
Department of Biochemistry, University of Illinois, Urbana-Champaign, Urbana, IL, USA; Cancer Center at Illinois, University of Illinois, Urbana-Champaign, Urbana, IL, USA.
Dev Cell. 2020 Mar 23;52(6):748-763.e6. doi: 10.1016/j.devcel.2020.01.037. Epub 2020 Feb 27.
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 RBFOX2 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 RBFOX2-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 RBFOX2 isoform in DM1 cardiac pathogenesis.
肌强直性营养不良 1 型（DM1）是一种多系统遗传性疾病，由 DMPK 基因 3'-非翻译区的 CTG 重复扩展引起。心脏功能障碍发生在约 80%的 DM1 患者中，是 DM1 相关死亡的第二大主要原因。在此，我们报告由于剪接因子和 microRNA 活性的改变，DM1 心脏组织中 RNA 结合蛋白 RBFOX2 的非肌肉剪接异构体的上调导致 DM1 个体的心脏传导缺陷。通过四环素诱导的转基因或 CRISPR/Cas9 介导的基因组编辑在心脏中表达非肌肉 RBFOX2 异构体的小鼠，重现了 DM1 相关的心脏传导延迟和心律失常的自发发作。此外，通过将 RNA 结合与来自 DM1 患者和表达非肌肉 RBFOX2 异构体的小鼠的心脏转录组数据集进行整合，我们鉴定出 RBFOX2 驱动的电压门控钠和钾通道中的剪接缺陷，改变了它们的电生理特性。因此，我们的研究结果揭示了异常表达的 RBFOX2 异构体在 DM1 心脏发病机制中的跨显性作用。
