Q373fs variant of <i>RBM20</i> affects splicing and expression of cardiac-related genes and cardiac function: human sudden death case and mouse experiments

RBM20 is one of the genes predisposing to dilated cardiomyopathy (DCM). Several dozen variants associated with DCM have been reported so far. Variants in the arginine/serine-rich domain and the RNA recognition motif domain have been well studied, but the pathogenicity of variants outside of these areas remains unknown. A patient with the Q373fs-RBM20 variant without a typical DCM phenotype was identified in a sudden death cohort. The Q374fs-Rbm20 mouse model was generated to determine the significance of this variant. In mouse experiments, cardiac dysfunction, such as reduced fractional shortening and an extended duration of QRS and the corrected QT interval, were observed in Q374fs-Rbm20 mice by ultrasound echocardiography and electrocardiography. RNA sequencing analysis showed that Q374fs-Rbm20 mice had different splicing patterns, such as Ttn, Ldb3, Camk2d, Obscn, and Ryr2. Casq1, Mybpc2, and Myot expression was also upregulated in Q374fs-Rbm20 mice. A 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. Our findings suggest that the Q374fs-Rbm20 variant changes gene splicing, affects genes involved in sarcomere structure and calcium handling genes, and presents with cardiac dysfunction.