Work

Mutational mapping of sequence variants within the arginine- and serine-rich domain of RNA binding motif protein 20

Year: 2026

Type: article

Abstract: Mutations in the cardiac splicing factor RNA binding motif protein 20 (RBM20) are associated with severe forms of dilated cardiomyopathy. Mutations predominate within the highly conserved RSRSP-stretch and are characterized by a cytoplasmic mislocalization of RBM20. However, a sequence downstream of the RSRSP-stretch, the SRSLSP-stretch, is also phylogenetically highly conserved. The impact of the SRSLSP-stretch is unclear. In our study we investigated subcellular localization of RBM20 variants in HEK293 cells after transient transfection. We showed that variants within the RSRSP-stretch lead to significant cytoplasmic mislocalization. Aberrant TTN-splicing was observed in the explanted myocardium of an RBM20-p.R634W carrier. Within the SRSLSP-stretch, variants at amino acid position 641 are associated with partial mislocalization of RBM20. Molecular modelling of RBM20 and transportin-3 interaction by AlphaFold-3 suggests that the RSRSP stretch and arginine at position 641 are involved in transportin-3 interaction. In summary, our study supports the functional relevance of the RSRSP-stretch for the RBM20-TNPO3 interaction, whereas variants within the adjacent SRSLSP stretch have a minor impact on the nuclear localization. Furthermore, the data underscore the limitations of in silico-based pathogenicity predictions of RBM20 variants.

Source: Biochemical and Biophysical Research Communications

DOI: 10.1016/j.bbrc.2026.154294