Mislocalization of pathogenic RBM20 variants in dilated cardiomyopathy is caused by loss-of-interaction with Transportin-3

Julia Kornienko, Marta Rodríguez-Martínez, Kai Fenzl, Florian Hinze, Daniel Schraivogel, Markus Grosch, Brigit Tunaj, Dominik Lindenhofer, Laura Schraft, Moritz Kueblbeck, Eric Smith, Chad Mao, Emily Brown, Anjali Owens, Ardan M. Saguner, Benjamin Meder, Victoria Parikh, Michael Gotthardt and Lars M. Steinmetz ()
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Julia Kornienko: Genome Biology Unit, European Molecular Biology Laboratory (EMBL)
Marta Rodríguez-Martínez: Genome Biology Unit, European Molecular Biology Laboratory (EMBL)
Kai Fenzl: Genome Biology Unit, European Molecular Biology Laboratory (EMBL)
Florian Hinze: Max Delbrück Center for Molecular Medicine in the Helmholtz Association
Daniel Schraivogel: Genome Biology Unit, European Molecular Biology Laboratory (EMBL)
Markus Grosch: Genome Biology Unit, European Molecular Biology Laboratory (EMBL)
Brigit Tunaj: Genome Biology Unit, European Molecular Biology Laboratory (EMBL)
Dominik Lindenhofer: Genome Biology Unit, European Molecular Biology Laboratory (EMBL)
Laura Schraft: Genome Biology Unit, European Molecular Biology Laboratory (EMBL)
Moritz Kueblbeck: Genome Biology Unit, European Molecular Biology Laboratory (EMBL)
Eric Smith: University of Michigan
Chad Mao: Children’s Healthcare of Atlanta & Emory University
Emily Brown: Johns Hopkins Hospital
Anjali Owens: University of Pennsylvania
Ardan M. Saguner: University Heart Center Zurich, University Hospital Zurich
Benjamin Meder: Angiology and Pulmology, University Hospital Heidelberg
Victoria Parikh: Stanford University School of Medicine
Michael Gotthardt: Max Delbrück Center for Molecular Medicine in the Helmholtz Association
Lars M. Steinmetz: Genome Biology Unit, European Molecular Biology Laboratory (EMBL)

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Severe forms of dilated cardiomyopathy (DCM) are associated with point mutations in the alternative splicing regulator RBM20 that are frequently located in the arginine/serine-rich domain (RS-domain). Such mutations can cause defective splicing and cytoplasmic mislocalization, which leads to the formation of detrimental cytoplasmic granules. Successful development of personalized therapies requires identifying the direct mechanisms of pathogenic RBM20 variants. Here, we decipher the molecular mechanism of RBM20 mislocalization and its specific role in DCM pathogenesis. We demonstrate that mislocalized RBM20 RS-domain variants retain their splice regulatory activity, which reveals that aberrant cellular localization is the main driver of their pathological phenotype. A genome-wide CRISPR knockout screen combined with image-enabled cell sorting identified Transportin-3 (TNPO3) as the main nuclear importer of RBM20. We show that the direct RBM20-TNPO3 interaction involves the RS-domain, and is disrupted by pathogenic variants. Relocalization of pathogenic RBM20 variants to the nucleus restores alternative splicing and dissolves cytoplasmic granules in cell culture and animal models. These findings provide proof-of-principle for developing therapeutic strategies to restore RBM20’s nuclear localization in RBM20-DCM patients.

Date: 2023
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DOI: 10.1038/s41467-023-39965-6

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