ArticleNature communications2023
Mislocalization of pathogenic RBM20 variants in dilated cardiomyopathy is caused by loss-of-interaction with Transportin-3.
Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 37 citations in OpenAlex.
- Image-enabled cell sorting permits prospective isolation of primitive hematopoietic stem cell subsets with distinct functional potential.Experimental hematology · 2026Article
- Novel Truncating Variant c.1222DupC inCirculation. Genomic and precision medicine · 2026Article
- The cardiac 4D nucleome: nuclear and chromatin dynamics across development, disease and ageing.Nature reviews. Cardiology · 2026Review
- Cytoplasmic RBM20 granules modulate non-RBM20 target splicing through interactions with other splicing factors.Nucleic acids research · 2026Article
- RBM20 variants disrupt CaSignal transduction and targeted therapy · 2026Article
- Technologies to measure and modulate protein subcellular localization.Nature reviews. Molecular cell biology · 2026Review
- Dysregulation of liquid-liquid phase separation: from molecular mechanisms to targeted therapies in cardiovascular diseases.Journal of nanobiotechnology · 2026Review
- Alternative Splicing of SCL30a Generates Distinct Isoforms to Modulate ABA Signaling in Arabidopsis.Plants (Basel, Switzerland) · 2026Article
- Multiple roads between the nucleus and the cytoplasm: classes of linear NLSs and NESs and their receptors.Current opinion in structural biology · 2026Review
- RBM20 isoform regulation by independent transcription start sites adapts alternative splicing in development and disease.Nature communications · 2026Article
- CAMK2D causes heart failure in mice with RBM20 cardiomyopathy.Nature cardiovascular research · 2026Article
- Forces that shape the transcriptome: Linking cellular mechanosensing to mRNA splicing.The Journal of biological chemistry · 2026Review
- Prime editing corrects the dilated cardiomyopathy causing RBM20-P633L-mutation in human cardiomyocytes.Molecular therapy. Nucleic acids · 2025Article
- Treating RBM20-related cardiomyopathy-Ready for prime time?Molecular therapy. Nucleic acids · 2025Article
- RBMS1 orchestrates cardiac hypertrophy by facilitating CTTN splice-switching and sarcomere dynamics.EMBO molecular medicine · 2025Article
- Alternative Splicing: Molecular Mechanisms, Biological Functions, Diseases, and Potential Therapeutic Targets.MedComm · 2025Review
- Functional phenotyping of genomic variants using joint multiomic single-cell DNA-RNA sequencing.Nature methods · 2025Article
- A ratiometric catalog of protein isoform shifts in the cardiac fetal gene program.JCI insight · 2025Article
- AAV9-Mediated TNPO3 Overexpression in the Heart Rescues RBM20 Cardiomyopathy in Mice.Circulation · 2025Article
- QKI ensures splicing fidelity during cardiogenesis by engaging the U6 tri-snRNP to activate splicing at weak 5' splice sites.bioRxiv : the preprint server for biology · 2025Article
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Authors and funding
19 authors at 11 institutions in 4 countries.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.