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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
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Mislocalization of pathogenic RBM20 variants in dilated cardiomyopathy is caused by loss-of-interaction with
Julia Kornienko1,2,3, Marta Rodríguez-Martínez1, Kai Fenzl1,3
1Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
Nature Communications
|July 18, 2023
Summary
Mutations in RBM20 cause dilated cardiomyopathy (DCM) by mislocalizing the protein. Restoring RBM20
Area of Science:
- Molecular Biology
- Genetics
- Cardiovascular Research
Background:
- Dilated cardiomyopathy (DCM) is linked to mutations in the splicing factor RBM20.
- Mutant RBM20 mislocalizes to the cytoplasm, forming toxic granules and disrupting gene splicing.
Purpose of the Study:
- To elucidate the molecular mechanism of RBM20 mislocalization in DCM pathogenesis.
- To identify therapeutic strategies for RBM20-related DCM.
Main Methods:
- Genome-wide CRISPR knockout screen.
- Image-enabled cell sorting.
- Cellular and animal models of DCM.
Main Results:
- Mislocalized RBM20 variants retain splicing activity; cytoplasmic mislocalization drives DCM.
- Transportin-3 (TNPO3) identified as the primary nuclear importer of RBM20.
- Pathogenic RBM20 variants disrupt the RBM20-TNPO3 interaction via the RS-domain.
Conclusions:
- Aberrant RBM20 localization, not altered splicing activity, is the primary driver of RBM20-DCM.
- Targeting the RBM20-TNPO3 interaction offers a therapeutic avenue.
- Restoring nuclear RBM20 resolves splicing defects and cytoplasmic granules in DCM models.
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