Q373fs variant of RBM20 affects splicing of cardiac genes that are causative for sudden death; Human sudden death case and animal experiment

RBM20 is one of the genes predisposing to dilated cardiomyopathy (DCM). Variants in the RS domain and the RNA-recognition motif have been well studied, but the pathogenicity of variants outside the hotspot remains unknown. A human patient with the Q373fs-RBM20 variant without a typical DCM phenotype was identified in sudden death cohorts. In the mouse experiments, RNA seq analysis revealed that Q374fs-Rbm20 mice showed some different splicing patterns in such as Ttn, Ldb3, Camk2d,Obscn, and Ryr2. The expressions of Casq1, Mybpc2, and Myot were also upregulated in Q374fs-Rbm20 mice. The pathway analysis indicated the involvement of some of the 1770 differentially expressed genes in Cytoplasmic ribosomal proteins Calcium regulation in cardiac cells and Striated muscle contraction. Cardiac dysfunction such as cardiac dilation and extended duration of QRS and QTc were observed by ultrasound echocardiography and Electro-cardiogram. The Q373fs-RBM20 (Q374fs-Rbm20) variant changes gene splicing and affects gene expression of sarcomere structural genes and Ca handling genes and presented cardiac dysfunction, suggesting that Q373fs-RBM20 human patient may cause arrhythmogenic sudden death. Overall design: Using the CRISPR/Cas system, we generated KI mice harboring the c.1121_1122delAG (p. Q374Rfs) variant in the mouse Rbm20 gene, which corresponded to human c.1118_1119delAG (p. Q373Rfs).