Deletion of the RS domain in RBM20 leads to dilated cardiomyopathy

Human patients carrying genetic mutations in RBM20 develop a clinically aggressive dilated cardiomyopathy (DCM) characterized by early onset heart failure, high mortality, and sudden death, which is recapitulated in animal models. RBM20 has two primary domains, an RNA recognition motif (RRM) that binds RNA and an arginine/serine (RS)-rich domain that mediates spliceosome assembly and nuclear localization. Reported data showed that mutations in the RS domain lead to severe DCM. Loss of the RRM domain in RBM20 has been shown to disrupt the splicing of RBM20 target transcripts but does not lead to DCM. The objectives of the present study were to determine the functional role of the RS domain in DCM and examine the mechanisms. Mice expressing RBM20 lacking the RS domain (Rbm20?RS) were generated using CRISPR/Cas9 technology. Male and female Rbm20?RS mice developed a DCM-like phenotype characterized by ventricular dilation and impaired systolic function, that is more severe in females. Splicing of RBM20 target genes, including Ttn, was disrupted in both Rbm20?RS and Rbm20?RRM mice. However, RBM20 was mis-localized to the sarcoplasm only in the hearts of Rbm20?RS mice, indicating that mis-localization of RBM20 rather than disrupted splicing is key in DCM pathogenesis. Overall design: The objectives of the present study were to determine the functional role of the RS domain in DCM and examine the mechanisms.