Identification of nuclear retention domains in the alternative splicing regulator RBM20

Abstract

RNA binding motif protein type 20 (RBM20) is a nuclear protein which regulates alternative splicing of expressed genes that have a key role in cardiac functions. Mutations in the RBM20 gene are linked to familial dilated cardiomyopathy and most of them alter residues in the RS domain of the protein. Functional motifs in the RBM20 protein have been poorly characterized. Our study provides functional annotations to structural domains within the RBM20 protein required for its nuclear localization. By cloning the human and mouse RBM20 genes, producing expressing vectors for truncated proteins and comparing their sub-cellular distribution in transfected cells, we have identified the sequences necessary for RBM20 full nuclear retention. The region overlaps both an RNA binding motif and a serine-arginine domain. The sequence is conserved in many species but belongs only to RBM20 protein orthologs. The RMB20 tissue specificity, together with the properties of its nuclear localization determinant, demonstrates a specific evolutionary selection for post-transcriptional regulation in the heart, highlighting RBM20 as a key factor for regulation of splicing events required for cardiac function