PDF(Pubmed)
Abstract：
We showed an association between atrial fibrillation and rare loss-of-function (LOF) variants in the cardiac splicing regulator RBM20 in 2 independent cohorts. In a rat model with loss of RBM20, we demonstrated altered splicing of sarcomere genes (NEXN, TTN, TPM1, MYOM1, and LDB3), and differential expression in key cardiac genes. We identified altered sarcomere and mitochondrial structure on electron microscopy imaging and found compromised mitochondrial function. Finally, we demonstrated that 3 novel LOF variants in RBM20, identified in patients with atrial fibrillation, lead to significantly reduced splicing activity. Our results implicate alternative splicing as a novel proarrhythmic mechanism in the atria.
摘要：
我们在2个独立的队列中显示了心脏剪接调节因子RBM20中心房颤动与罕见功能丧失（LOF）变异之间的关联。在RBM20缺失的大鼠模型中，我们证明了肌节基因的剪接改变（NEXN，TTN,TPM1、MYOM1和LDB3)，和关键心脏基因的差异表达。我们在电子显微镜成像中鉴定了改变的肌节和线粒体结构，并发现线粒体功能受损。最后,我们证明了RBM20中的3种新的LOF变异，在房颤患者中发现，导致剪接活性显著降低。我们的结果暗示选择性剪接是心房中一种新型的心律失常机制。
