Affinage

RBM20

RNA-binding protein 20 · UniProt Q5T481

Length
1227 aa
Mass
134.3 kDa
Annotated
2026-06-10
100 papers in source corpus 37 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RBM20 is a muscle-specific RNA-binding splicing repressor that governs a cardiac alternative-splicing program centered on titin (TTN) and roughly 30 other heart genes, with loss-of-function causing pathological titin isoform shifts and dilated cardiomyopathy (PMID:22466703). It represses exon inclusion by binding UCUU elements predominantly in introns flanking alternative exons, where its RRM domain—extended by a C-terminal helix that undergoes coupled folding-binding upon engaging the final uracil—confers affinity and specificity for the motif (PMID:32187365), while the RRM, ZnF2, and C-terminus together are necessary and sufficient for repressor activity (PMID:29518215). RBM20 stalls the spliceosome at complex A through interactions with U1 and U2 snRNPs, and assembles on nascent TTN pre-mRNA into nuclear foci (PMID:24960161, PMID:23307558). These foci nucleate a cardiac trans-interacting chromatin domain or 'splicing factory' that brings the TTN locus into spatial proximity with other RBM20 targets including CACNA1C and CAMK2D to co-regulate their splicing (PMID:30948719). Beyond titin, RBM20 controls isoform switching of CAMK2D/CaMKIIδ, CACNA1C, FHOD3, and ENH, and supplies the substrate for a class of titin circular RNAs (PMID:29650543, PMID:27531932, PMID:31717392, PMID:30468920). Nuclear import of RBM20 is mediated by Transportin-3 (TNPO3) via the RS/RSRSP domain, whose serine residues are constitutively phosphorylated by SRPK1, CLK1, and AKT2 (PMID:37463913, PMID:29895960, PMID:36140694). Pathogenic missense variants in the RSRSP stretch disrupt TNPO3 binding and nuclear import, driving cytoplasmic mislocalization and the formation of liquid-like RNP granules that fuse with stress granules and drive cardiomyopathy independently of splicing loss (PMID:37463913, PMID:33188278, PMID:37219949). Aberrant CAMK2D splicing and functional CAMK2D overactivation are central mediators of the resulting heart failure and arrhythmia (PMID:42082791), and ASO-mediated RBM20 downregulation, adenine base editing, and CAMK2 inhibition rescue disease in animal models (PMID:34851694, PMID:36417486, PMID:42082791, PMID:40242865).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2012 High

    Established RBM20 as a disease gene by showing its loss disrupts titin splicing, defining the first molecular function for the protein.

    Evidence Positional cloning and cardiac transcriptome deep sequencing in a mutant rat strain, confirmed in human

    PMID:22466703

    Open questions at the time
    • Did not define the RNA motif or binding mechanism
    • Did not establish how splicing regulation translates to cardiomyopathy
  2. 2013 High

    Showed RBM20 represses splicing by binding titin pre-mRNA and forms nuclear speckles on partially processed transcripts, beginning to localize its mechanism of action.

    Evidence RNA binding assays, immunofluorescence, splicing reporters, and knockout rat

    PMID:23307558 PMID:23886709

    Open questions at the time
    • Spliceosomal partners not yet identified
    • Genome-wide binding map absent
  3. 2014 High

    Defined the UCUU recognition motif and the step of spliceosome inhibition, explaining how RBM20 represses exon inclusion at the molecular level.

    Evidence Transcriptome-wide CLIP-seq, RNA-seq, and quantitative proteomics identifying U1/U2 snRNP interaction

    PMID:24960161

    Open questions at the time
    • Structural basis of UCUU recognition unresolved
    • Mechanism of complex A stalling not detailed
  4. 2016 High

    Connected RBM20 splicing to functional outputs by showing it generates titin circRNAs and tuning titin compliance, broadening its target repertoire.

    Evidence CircRNA profiling and RRM-deletion mice with passive stiffness measurements

    PMID:27289039 PMID:27531932 PMID:27630136

    Open questions at the time
    • Functional role of titin circRNAs unclear
    • Cooperative regulation with other RBPs incompletely mapped
  5. 2018 High

    Identified CAMK2D mis-splicing and calcium handling defects as a downstream consequence linking RBM20 loss to arrhythmia, and mapped the domain requirements for repression.

    Evidence Knockout mice/rats, patch-clamp electrophysiology, Ca2+ imaging, pharmacological rescue, and truncation/domain analysis

    PMID:29518215 PMID:29650543 PMID:29725258 PMID:30468920

    Open questions at the time
    • Causal sufficiency of CAMK2D not yet tested genetically
    • RS-domain contribution to phenotype not separated from splicing loss
  6. 2018 High

    Established that RSRSP-stretch phosphorylation is constitutive and that disrupting this region impairs nuclear localization and causes DCM, shifting attention from splicing loss toward localization.

    Evidence Phospho-antibody staining and S637A knock-in mouse with titin isoform analysis

    PMID:29895960

    Open questions at the time
    • Importer mediating nuclear entry not identified
    • Mechanism of phosphorylation control of import unclear
  7. 2019 High

    Revealed a 3D-genome 'splicing factory' nucleated by TTN pre-mRNA that spatially organizes multiple RBM20 targets, providing a higher-order organizational principle for its regulation.

    Evidence Hi-C, RNA-seq, ATAC-seq, and CRISPR editing in iPSC-derived cardiomyocytes

    PMID:30948719 PMID:31614708 PMID:31717392

    Open questions at the time
    • Protein scaffolds organizing the factory not fully defined
    • Causality of chromatin proximity for splicing efficiency partial
  8. 2020 High

    Demonstrated that pathogenic variants produce gain-of-function cytoplasmic RNP granules with liquid-like properties, identifying a splicing-independent disease mechanism.

    Evidence Gene-edited pigs, patient iPSC-CMs, eCLIP, super-resolution microscopy, and condensate biochemistry

    PMID:33110103 PMID:33188278 PMID:34732726

    Open questions at the time
    • Granule composition and toxicity mechanism incomplete
    • Relative contribution of granules vs splicing loss not yet dissected in vivo
  9. 2020 High

    Solved the RRM–UCUU structure showing coupled folding-binding of a C-terminal helix, explaining motif specificity at atomic resolution.

    Evidence NMR structure determination with affinity assays and helix mutagenesis

    PMID:29518215 PMID:32187365

    Open questions at the time
    • Structure of RBM20 engaged with spliceosome unknown
    • Higher-order RNA clustering geometry undefined
  10. 2020 Medium

    Showed RBM20 expression is tunable by circadian and pharmacological inputs, including retinoic acid rescue of haploinsufficiency, opening expression-based therapeutic strategies.

    Evidence Bmal1 KO mice, iPSC-CMs with retinoic acid treatment, splicing and contractility readouts

    PMID:28676430 PMID:32905764 PMID:36047761

    Open questions at the time
    • Direct transcriptional control circuitry partial
    • Translatability of retinoic acid rescue unconfirmed
  11. 2022 High

    Genetically separated RS-domain-dependent localization from RRM-dependent splicing, establishing mislocalization/granule formation as the critical driver of severe DCM.

    Evidence RS-deletion vs RRM-deletion mouse models and S639G knock-in mice with echocardiography and RNA-seq

    PMID:35041844 PMID:37219949

    Open questions at the time
    • Molecular toxicity of cytoplasmic granules not fully resolved
    • Why frame-shift mutants are milder than RS mutants not fully explained
  12. 2022 Medium

    Identified SRPK1, CLK1, and AKT2 as RSRSP-stretch kinases regulating target splicing, and catalogued RBM20 phosphosites controlling transport and condensation.

    Evidence In vitro/in vivo kinase assays, middle-down mass spectrometry, phosphomimetic mutants, and splicing reporters

    PMID:35394688 PMID:36140694

    Open questions at the time
    • Single-lab kinase findings
    • Whether phosphorylation directly gates transport unresolved (phosphomimetics not sufficient in vitro)
  13. 2022 High

    Validated therapeutic RBM20 reduction by ASO and correction by adenine base editing, demonstrating that restoring localization and splicing rescues cardiac function.

    Evidence ASO in mice and engineered human heart tissue; adenine base editing in iPSC-CMs and AAV delivery in knock-in mice

    PMID:34851694 PMID:36417486

    Open questions at the time
    • Long-term safety and off-target effects of base editing unaddressed
    • Optimal therapeutic window for RBM20 dosing undefined
  14. 2023 Medium

    Extended RBM20 phenotypes to atrial fibrillation and mitochondrial/structural defects, and linked drug-induced RBM20 suppression to pathogenic fetal isoform switching.

    Evidence Rat LOF model with electron microscopy and mitochondrial assays; sorafenib treatment with RBM20 rescue and ATP synthesis assays

    PMID:38006979 PMID:38510713

    Open questions at the time
    • Mechanism linking RBM20 to mitochondrial structure incomplete
    • Single-lab observations
  15. 2024 Medium

    Mapped the protein and chromatin architecture of the TTN-centered RNA factory and showed RBM20 loss remodels its scaffolding factors, deepening the splicing-factory model.

    Evidence O-MAP proximity interactome mapping with genome editing (preprint)

    PMID:39574693

    Open questions at the time
    • Preprint, single lab
    • Functional roles of recruited factors QKI/SAFB not established
  16. 2025 High

    Demonstrated that reducing cytoplasmic RNP granules alleviates DCM without restoring target splicing, and that atrial cytoplasmic mutant RBM20 drives arrhythmia independently of splicing, cementing granule toxicity as a splicing-independent disease mechanism.

    Evidence ASO in S639G knock-in mice with granule quantification; atrial-specific mutant RBM20 mouse with ECG and Ca2+ imaging

    PMID:40242865 PMID:40480405

    Open questions at the time
    • Precise biochemical mechanism of granule-driven dysfunction unresolved
    • Connexin 43 mislocalization mechanism incomplete
  17. 2026 High

    Established CAMK2D as causally required for RBM20 cardiomyopathy through genetic epistasis and pharmacological rescue, identifying functional CAMK2D overactivation as a key downstream effector.

    Evidence Rbm20/Camk2d double-knockout mice, splice-variant re-expression, hesperadin treatment, and phosphoproteomics

    PMID:42059065 PMID:42082791

    Open questions at the time
    • Relative weighting of CAMK2D vs titin/granule pathways unclear
    • Translatability of CAMK2 inhibition to patients untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the relative contributions of splicing loss, RNP-granule toxicity, and CAMK2D overactivation combine to produce specific cardiac phenotypes, and whether RBM20 functions outside cardiac/skeletal muscle, remain unresolved.
  • Quantitative dissection of parallel disease mechanisms lacking
  • Non-cardiac roles (e.g., Tau splicing) only weakly evidenced

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 4 GO:0140110 transcription regulator activity 3 GO:0045182 translation regulator activity 2
Localization
GO:0005829 cytosol 4 GO:0005634 nucleus 3 GO:0005654 nucleoplasm 3
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-397014 Muscle contraction 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
AKT2CLK1PTBP1RBM24SRPK1TNPO3
Complex memberships
TTN-locus splicing factory / trans-interacting chromatin domain

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 Loss-of-function mutation in RBM20 causes pathological titin isoform expression; RBM20 regulates alternative splicing of titin (TTN) and approximately 30 other cardiac genes conserved between humans and rats, identified by positional cloning in a rat strain with altered titin mRNA splicing and confirmed by deep sequencing of the cardiac transcriptome. Positional cloning, deep RNA sequencing (transcriptome), loss-of-function rat model Nature medicine High 22466703
2014 RBM20 acts as a splicing repressor by binding predominantly within intronic regions near 3' and 5' splice sites via a distinct RNA-recognition element (UCUU motif); RBM20 interacts with U1 and U2 snRNPs and represses splicing by stalling the spliceosome at complex A. Transcriptome-wide CLIP-seq, RNA-seq, quantitative proteomics (mass spectrometry), cell culture and rat/human hearts The Journal of clinical investigation High 24960161
2013 RBM20 mediates titin exon skipping by binding to titin pre-mRNA to repress splicing of specific regions; RBM20 nuclear speckles are aggregates of RBM20 protein on partially processed titin pre-mRNAs; RBM20 also mediates intron retention and exon shuffling; cooperative repression and alternative 3' splice site selection are used to skip different subsets of titin exons. RNA binding assays, immunofluorescence, splicing reporter assays, knockout rat model Nucleic acids research High 23307558
2018 Phosphorylation of the two serine residues in the RSRSP stretch of RBM20 (S638 and S640 in rats) is constitutive; mutations in this stretch disrupt nuclear localization of RBM20; the RSRSP stretch functions as a critical part of a nuclear localization signal, and S637A knock-in mice display titin isoform changes and DCM-like phenotype. Phospho-antibody staining, knock-in mouse model (Rbm20 S637A), titin isoform analysis Scientific reports High 29895960
2018 Loss of RBM20 causes aberrant splicing of CaMKIIδ, shifting expression toward the δ-A isoform that activates L-type Ca2+ current (ICa,L), resulting in increased ICa,L, intracellular Ca2+ overload, increased sarcoplasmic reticulum Ca2+ content, and spontaneous Ca2+ releases; verapamil (ICa,L antagonist) attenuated these proarrhythmic effects. Rbm20 knockout mice, cellular electrophysiology patch-clamp, intracellular Ca2+ measurements, pharmacological rescue Circulation High 29650543
2018 The RRM domain and C-terminus of RBM20 are necessary and sufficient for splicing repressor activity; the ZnF2 domain is important for splicing repression; RBM20 binds titin pre-mRNA clusters through the RRM domain and represses upstream and downstream introns; PTB4 is a novel titin splice regulator that counteracts RBM20 repressor activity. Tissue culture splice reporter assay, in vitro RNA binding assay, truncation mutants Nucleic acids research High 29518215
2019 TTN pre-mRNA nucleates RBM20 foci in the nucleus that drive spatial proximity between the TTN locus and other inter-chromosomal RBM20 targets (CACNA1C, CAMK2D), forming a cardiac-specific trans-interacting chromatin domain (TID) functioning as a splicing factory; genome editing studies confirmed this mechanism promotes RBM20-dependent alternative splicing. Hi-C, RNA-seq, ATAC-seq, genome editing (CRISPR), iPSC-derived cardiomyocytes Nature communications High 30948719
2020 RBM20 R636S pathogenic variant causes accumulation of dysregulated RNP granules with liquid-like material properties in the sarcoplasm of cardiomyocytes; these granules dock at spaced intervals along cytoskeletal elements, promote phase partitioning of cardiac biomolecules, and fuse with stress granules; confirmed in gene-edited pigs and patient myocardium. RBM20 gene-edited pigs (R636S homozygous), iPSC-derived cardiomyocytes from patients, live-cell imaging, biochemical analysis of condensates Nature medicine High 33188278
2020 RBM20 nuclear localization is mediated by Transportin-3 (TNPO3) as the main nuclear importer; the direct RBM20–TNPO3 interaction involves the RS domain and is disrupted by pathogenic variants; mislocalized RS-domain mutants retain splice regulatory activity, indicating aberrant cytoplasmic localization (not loss of splicing activity) is the main driver of pathological phenotype; relocalization of mutant RBM20 to nucleus restores splicing and dissolves cytoplasmic granules. Genome-wide CRISPR knockout screen with image-enabled cell sorting, Co-IP/pulldown (RBM20–TNPO3 interaction), cell culture and animal model rescue experiments Nature communications High 37463913
2021 DCM-associated missense mutations in RBM20 (e.g., R636S) cause gain-of-function: mutant RBM20 shifts RNA binding preference to 3' UTR sequences shared with ALS-associated RBPs (FUS, DDX6); mutant RBM20 localizes to cytoplasmic processing bodies (DDX6+) under basal conditions and to stress granules (G3BP1+) under acute stress; these mutations produce unique splicing, polyadenylation, and circular RNA defects distinct from KO. eCLIP, deep RNA-seq, super-resolution microscopy, isogenic iPSC lines with missense mutations and KO, engineered heart tissues Nature communications High 34732726
2022 Disruption of the RS domain (nuclear localization signal) is causative for DCM; Rbm20ΔRS mice develop DCM with RBM20 mislocalization to sarcoplasm and granule formation similar to pathogenic mutation knock-in animals; in contrast, mice lacking the RRM domain show mis-splicing but no DCM and no granule formation, establishing that RS domain-mediated nuclear localization (not splicing loss per se) is the critical mechanism for severe DCM. RS domain deletion knock-in mouse model, RRM deletion mouse model, immunocytochemistry, echocardiography, RNA-seq JCI insight High 37219949
2022 RBM20 S639G mutation promotes RBM20 trafficking to sarcoplasm and RNP granule formation, causing severe DCM and ~50% premature mortality in homozygous mice; this demonstrates RNP granules as a driver of cardiomyopathy. S639G knock-in mouse model, fluorescent immunohistochemistry, RNA-seq, echocardiography, electrocardiography Journal of molecular and cellular cardiology High 35041844
2022 SRPK1, CLK1, and AKT2 all phosphorylate S638 and S640 in the RSRSP stretch of RBM20 in vitro and in vivo, and this phosphorylation regulates RBM20 target gene splicing. In vitro kinase assays, in vivo studies with kinase overexpression/inhibition, splicing reporter assays Genes Medium 36140694
2022 Using middle-down mass spectrometry, 16 phosphorylation sites were identified in RBM20, including S638 and S640 in the RSRSP stretch; mutations on these sites regulated splicing and promoted nucleocytoplasmic transport and protein-RNA condensate formation in vitro; phosphomimetic mutations indicated phosphorylation was not the major direct cause of nucleocytoplasmic transport in vitro. Middle-down mass spectrometry, S637A knock-in mouse, in vitro phosphomimetic mutants, RNA-seq FASEB journal Medium 35394688
2020 RBM20 is required for the formation of a subset of titin circRNAs originating from the RBM20-regulated I-band region of the titin transcript; RBM20-null mice completely lack these titin circRNAs; by excluding specific exons from pre-mRNA, RBM20 provides the substrate for this class of circRNAs. CircRNA profiling of human hearts, RBM20-null mice, cardiac samples from RBM20 mutation carriers Circulation research High 27531932
2020 RBM20 RRM domain deletion (Rbm20ΔRRM) results in expression of large, supercompliant titin isoforms (N2BAsc) in the heart; partial RBM20 inhibition using this allele reduces titin-based passive stiffness and improves diastolic function in TAC/DOCA heart failure mice, demonstrating the causal role of RBM20-regulated titin isoform switching in diastolic function. Conditional RRM-deletion mice, TAC/DOCA surgery, echocardiography, pressure-volume analysis, passive stiffness measurements on LV muscle strips Circulation High 27630136
2019 RBM20 regulates the inclusion of CACNA1C exon 9*, with overexpression promoting exon 9* inclusion and knockdown causing skipping; RBM20 binds introns flanking exon 9* as shown by RNA immunoprecipitation; RBM20 overexpression reduces L-type Ca2+ currents and CaV1.2 membrane surface expression in neonatal rat cardiomyocytes. RBM20 overexpression and siRNA knockdown in neonatal rat cardiomyocytes, RNA immunoprecipitation, patch-clamp electrophysiology, surface expression assays International journal of molecular sciences Medium 31717392
2016 RBM20 and RBM24 cooperate to promote expression of short ENH splice variants by binding the 5' intronic region of exon 11 of the enh gene; expression of both RBPs is repressed by hypertrophic stimulations. Co-overexpression splicing assays, RNA binding assay (identification of binding region) FEBS letters Medium 27289039
2018 RBM20 and PTBP1 regulate alternative splicing of FHOD3 by promoting the shift from exon inclusion to exon exclusion; RBM20 targets the FHOD3 transcript, impacting actin filament organization in cardiac tissue. Splicing assays in cell lines, expression of RBM20 and PTBP1, RT-PCR of FHOD3 variants The international journal of biochemistry & cell biology Medium 30468920
2013 Sequences necessary for RBM20 full nuclear retention overlap the RNA binding motif (RRM) and the serine-arginine (RS) domain; this nuclear retention signal is conserved in RBM20 orthologs across species. Cloning of truncated RBM20 expressing vectors, subcellular distribution analysis in transfected cells FEBS letters Medium 23886709
2017 Insulin activates the PI3K-Akt-mTOR kinase axis in neonatal rat cardiomyocytes, leading to increased N2B titin isoform expression in an RBM20-dependent manner; inhibition of this axis reduces N2B in NRCMs and in diabetic rats in an RBM20-dependent manner; p70S6K1 knockdown reduces RBM20 levels while 4E-BP1 knockdown elevates them. Kinase inhibitors, siRNA knockdown (p70S6K1, 4E-BP1), primary neonatal rat cardiomyocytes, diabetic rat model, RT-PCR for titin isoforms Biochimica et biophysica acta. Molecular basis of disease Medium 28676430
2019 Angiotensin II promotes RBM20 transcription through activation of the MAPK/ELK1 signaling pathway; ELK1 binds the RBM20 promoter and a dual-luciferase assay confirmed Ang II-driven ELK1-mediated RBM20 transcription; increased RBM20 expression then regulates titin and other pre-mRNA splicing targets. Western blotting (MAPK activation), dual-luciferase promoter assay, primary cardiomyocyte treatment with Ang II/insulin/T3 International journal of molecular sciences Medium 31614708
2021 Antisense oligonucleotides (ASOs) targeting RBM20 increase expression of compliant titin isoforms in adult mice and improve cardiac function in a mouse model of increased wall stiffness; ASO treatment also reduced RBM20 to <50% in human engineered heart tissue, resulting in adapted relaxation kinetics. ASO treatment in adult mice, echocardiography, conductance catheter, RNA-seq, human engineered heart tissue Science translational medicine High 34851694
2020 Nuclear localization mutations in the RBM20 RS domain (S637A) cause RBM20 to accumulate in cytoplasmic perinuclear granule-like structures in cardiomyocytes; S637A knock-in mice (mimicking patient mutation) develop severe cardiac dysfunction and spontaneous atrial fibrillation/ventricular arrhythmias; in contrast, frame-shift deletion mutants show less severe phenotypes despite equivalent loss of RBM20-dependent splicing. S637A knock-in mouse model, immunofluorescence (nuclear vs. cytoplasmic localization), echocardiography, ECG Scientific reports High 33110103
2022 Adenine base editing (ABE) correction of RBM20 R634Q mutation in human iPSCs achieved 92% editing efficiency, normalizing alternative splicing of cardiac genes, restoring nuclear localization of RBM20, and eliminating cytoplasmic RNP granule formation; systemic AAV delivery of ABE in Rbm20R636Q mice restored cardiac function and extended lifespan. Adenine base editing in human iPSC-CMs, prime editing in iPSCs, AAV9 delivery in knock-in mice, RNA-seq, echocardiography Science translational medicine High 36417486
2020 All-trans retinoic acid upregulates RBM20 expression and reverts splicing, calcium handling, and contractility defects in iPSC-CMs with different causal RBM20 mutations, establishing that pharmacological upregulation of RBM20 can rescue haploinsufficiency. CRISPR/Cas9-engineered iPSC-CMs, all-trans retinoic acid treatment, RNA-seq for splicing, calcium imaging, contractility measurement Cell reports Medium 32905764
2025 Reducing cytoplasmic RNP granules via ASO-mediated downregulation of Rbm20 in Rbm20 S639G knock-in mice alleviates DCM without restoring mis-splicing of target genes (including TTN, CAMK2D, RYR2, ANK3), demonstrating that RNP granules are a critical driver of RBM20 cardiomyopathy independent of splicing dysregulation. ASO treatment in S639G knock-in mice, quantitative immunohistochemistry for RNP granules, echocardiography, RT-PCR for splicing, ECG, Ca2+ release-reuptake kinetics Circulation research High 40242865
2020 RBM20 regulates cardiomyopathy-relevant genes such as CaMKIIδ by controlling alternative splicing; in cardiomyocytes with RBM20 loss, aberrant CAMK2D splicing produces an isoform that activates downstream Ca2+ signaling, and loss of RBM20 caused altered expression of titin-binding partners and calcium handling proteins. Rbm20 knockout rats, gene expression array (Affymetrix), QPCR, western blotting, intracellular Ca2+ measurement in isolated cardiomyocytes International journal of biological sciences Medium 29725258
2026 CAMK2D is causally involved in RBM20 cardiomyopathy: Rbm20/Camk2d double knockout mice are protected from heart failure and sudden cardiac death; in Rbm20-deficient hearts, CAMK2D target phosphorylation is increased indicating functional CAMK2D overactivation (not only mis-splicing); re-expression of individual CAMK2D splice variants in double KO mice reintroduced cardiac dysfunction; treatment with CAMK2 inhibitor hesperadin improved cardiac function in Rbm20 R636Q knock-in mice. Double knockout mice (Rbm20/Camk2d), CAMK2D splice variant re-expression, CAMK2 inhibitor hesperadin treatment, phosphoproteomic analysis, echocardiography Nature cardiovascular research High 42082791
2020 RBM20 nuclear speckles localize to sites of TTN pre-mRNA transcription in muscle nuclei; the ZnF2 domain contributes to splicing repression activity in combination with the RRM and C-terminus domains. Cell culture splice reporter assay, domain truncation analysis Nucleic acids research Medium 29518215
2020 Structural determination of the RBM20 RRM domain bound to UCUU RNA reveals that the RRM domain spans a larger region than initially proposed; the C-terminal helix (encoded by exon 8) undergoes coupled folding-binding upon interaction with the final uracil of the UCUU motif, and removing this helix reduces both affinity and specificity for the UCUU motif. NMR structure determination, affinity binding assays, mutagenesis of the C-terminal helix Nucleic acids research High 32187365
2022 The skeletal muscle circadian clock regulates titin isoform expression through transcriptional regulation of Rbm20; Bmal1 knockout in skeletal muscle reduces Rbm20 expression, altering titin splicing and sarcomere length heterogeneity; this link was confirmed by environmental circadian disruption which also downregulated Rbm20. Inducible skeletal muscle-specific Bmal1 KO mice, RNA-seq, liquid chromatography-mass spectrometry, SDS-PAGE for titin isoforms, U7 snRNP-mediated splicing intervention eLife Medium 36047761
2023 Loss-of-function variants in RBM20 are associated with early-onset atrial fibrillation; in a rat model with loss of RBM20, altered splicing of sarcomere genes (NEXN, TTN, TPM1, MYOM1, LDB3) and differential expression in cardiac genes were demonstrated, along with altered sarcomere and mitochondrial structure and compromised mitochondrial function. Rat loss-of-function model, electron microscopy, mitochondrial function assays, RNA-seq, splicing activity assay for novel LOF variants JACC. Basic to translational science Medium 38510713
2024 O-MAP targeting TTN pre-mRNA introns mapped the molecular architecture of a muscle-specific nuclear RNA factory organized around the TTN locus; RBM20 loss remodels nearly every facet of this architecture including cis- and trans-interacting chromosomal domains and the recruitment of RNA-binding and chromatin-scaffolding factors (QKI, SAFB) along with their target transcripts. Oligonucleotide-mediated proximity-interactome mapping (O-MAP) targeting TTN pre-mRNA, chromatin loci/RNA/protein mapping, genome editing to remove RBM20 bioRxivpreprint Medium 39574693
2025 Cytoplasmic mutant RBM20 (S637A) expressed specifically in atria causes spontaneous atrial tachycardia and increased AF inducibility independent of atrial structural remodeling or heart failure; mutant RBM20 in atria causes decreased and mislocalized connexin 43, abnormal Ca2+ handling, and altered phosphorylation of Ca2+-handling proteins—mechanisms independent of splicing regulation. Atrial-specific mutant RBM20 expression mouse model (SlnCre/+; LSL-Rbm20S637A), ECG, programmed stimulation, immunofluorescence, Ca2+ imaging Journal of molecular and cellular cardiology Medium 40480405
2023 Sorafenib inhibits RBM20 expression in rat hearts and human cardiomyocytes; this causes alternative splicing of RBM20 targets SLC25A3 and FHOD3 into fetal isoforms with decreased function; upregulation of RBM20 during sorafenib treatment reversed pathogenic splicing and enhanced mitochondrial phosphate transport by SLC25A3. Rat heart transcriptomics, human cardiomyocyte treatment, RBM20 overexpression rescue, ATP synthesis assays Pharmacological research Medium 38006979
2026 A novel truncating RBM20 variant (c.1222DupC) introduces a premature termination codon generating a ~55 kDa truncated protein with complete loss of splicing activity and no dominant-negative effect on wild-type RBM20; the truncated protein localizes to both cytoplasm and nucleus but lacks RS and RRM domains; heterozygous iPSC-CMs show splicing defects in canonical targets (TTN, RYR2, CAMK2D, CACNA1G) and increased calcium transients, consistent with haploinsufficiency. Splicing reporter assays in HEK293 and neonatal rat cardiomyocytes, heterozygous iPSC-CMs, western blot, RT-PCR, RNA-seq, Ca2+ imaging Circulation. Genomic and precision medicine Medium 42059065
2026 RBM20 regulates Tau exon 6 and exon 10 alternative splicing as demonstrated by RNA-binding assays and qPCR in cell lines and neuronal organoids. RNA-binding assay, qPCR, cerebral organoid differentiation International journal of molecular sciences Low 42123583

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing. Nature medicine 480 22466703
2016 RBM20 Regulates Circular RNA Production From the Titin Gene. Circulation research 245 27531932
2018 RBM20 Mutations Induce an Arrhythmogenic Dilated Cardiomyopathy Related to Disturbed Calcium Handling. Circulation 189 29650543
2014 RNA-binding protein RBM20 represses splicing to orchestrate cardiac pre-mRNA processing. The Journal of clinical investigation 186 24960161
2010 Identification of novel mutations in RBM20 in patients with dilated cardiomyopathy. Clinical and translational science 152 20590677
2011 Genetic variation in the alternative splicing regulator RBM20 is associated with dilated cardiomyopathy. Heart rhythm 139 22004663
2022 Precise genomic editing of pathogenic mutations in RBM20 rescues dilated cardiomyopathy. Science translational medicine 130 36417486
2019 Dynamics of genome reorganization during human cardiogenesis reveal an RBM20-dependent splicing factory. Nature communications 125 30948719
2019 Regional Variation in RBM20 Causes a Highly Penetrant Arrhythmogenic Cardiomyopathy. Circulation. Heart failure 122 30871351
2013 Rbm20 regulates titin alternative splicing as a splicing repressor. Nucleic acids research 122 23307558
2016 Experimentally Increasing the Compliance of Titin Through RNA Binding Motif-20 (RBM20) Inhibition Improves Diastolic Function In a Mouse Model of Heart Failure With Preserved Ejection Fraction. Circulation 102 27630136
2020 Dysregulated ribonucleoprotein granules promote cardiomyopathy in RBM20 gene-edited pigs. Nature medicine 96 33188278
2017 Severe DCM phenotype of patient harboring RBM20 mutation S635A can be modeled by patient-specific induced pluripotent stem cell-derived cardiomyocytes. Journal of molecular and cellular cardiology 78 28941705
2015 Modeling structural and functional deficiencies of RBM20 familial dilated cardiomyopathy using human induced pluripotent stem cells. Human molecular genetics 76 26604136
2019 Pathogenic RBM20-Variants Are Associated With a Severe Disease Expression in Male Patients With Dilated Cardiomyopathy. Circulation. Heart failure 74 30871348
2013 Whole exome sequencing identifies a causal RBM20 mutation in a large pedigree with familial dilated cardiomyopathy. Circulation. Cardiovascular genetics 57 23861363
2018 Phosphorylation of the RSRSP stretch is critical for splicing regulation by RNA-Binding Motif Protein 20 (RBM20) through nuclear localization. Scientific reports 55 29895960
2018 Alternative Splicing Regulator RBM20 and Cardiomyopathy. Frontiers in molecular biosciences 54 30547036
2020 iPSC Modeling of RBM20-Deficient DCM Identifies Upregulation of RBM20 as a Therapeutic Strategy. Cell reports 53 32905764
2020 New Insights in RBM20 Cardiomyopathy. Current heart failure reports 52 32789749
2021 Gain-of-function cardiomyopathic mutations in RBM20 rewire splicing regulation and re-distribute ribonucleoprotein granules within processing bodies. Nature communications 50 34732726
2014 Rbm20-deficient cardiogenesis reveals early disruption of RNA processing and sarcomere remodeling establishing a developmental etiology for dilated cardiomyopathy. Human molecular genetics 46 24584570
2016 Reducing RBM20 activity improves diastolic dysfunction and cardiac atrophy. Journal of molecular medicine (Berlin, Germany) 42 27889803
2021 RBM20-Related Cardiomyopathy: Current Understanding and Future Options. Journal of clinical medicine 41 34575212
2020 A missense mutation in the RSRSP stretch of Rbm20 causes dilated cardiomyopathy and atrial fibrillation in mice. Scientific reports 41 33110103
2021 Therapeutic inhibition of RBM20 improves diastolic function in a murine heart failure model and human engineered heart tissue. Science translational medicine 38 34851694
2013 Pathophysiological defects and transcriptional profiling in the RBM20-/- rat model. PloS one 36 24367651
2020 The Emerging Role of the RBM20 and PTBP1 Ribonucleoproteins in Heart Development and Cardiovascular Diseases. Genes 34 32276354
2018 Molecular basis of titin exon exclusion by RBM20 and the novel titin splice regulator PTB4. Nucleic acids research 33 29518215
2017 RBM20, a potential target for treatment of cardiomyopathy via titin isoform switching. Biophysical reviews 33 28577155
2023 Mislocalization of pathogenic RBM20 variants in dilated cardiomyopathy is caused by loss-of-interaction with Transportin-3. Nature communications 32 37463913
2018 Splicing Factor RBM20 Regulates Transcriptional Network of Titin Associated and Calcium Handling Genes in The Heart. International journal of biological sciences 32 29725258
2016 Pharmacological Modulation of Calcium Homeostasis in Familial Dilated Cardiomyopathy: An In Vitro Analysis From an RBM20 Patient-Derived iPSC Model. Clinical and translational science 31 27105042
2020 Cardiomyopathy-associated mutations in the RS domain affect nuclear localization of RBM20. Human mutation 30 32840935
2017 Insulin regulates titin pre-mRNA splicing through the PI3K-Akt-mTOR kinase axis in a RBM20-dependent manner. Biochimica et biophysica acta. Molecular basis of disease 29 28676430
2013 Identification of nuclear retention domains in the RBM20 protein. FEBS letters 29 23886709
2016 RBM20 and RBM24 cooperatively promote the expression of short enh splice variants. FEBS letters 26 27289039
2022 RBM20 phosphorylation and its role in nucleocytoplasmic transport and cardiac pathogenesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 25 35394688
2021 The Combined Human Genotype of Truncating TTN and RBM20 Mutations Is Associated with Severe and Early Onset of Dilated Cardiomyopathy. Genes 25 34201072
2024 Mechanisms of RBM20 Cardiomyopathy: Insights From Model Systems. Circulation. Genomic and precision medicine 24 38288598
2022 RBM20S639G mutation is a high genetic risk factor for premature death through RNA-protein condensates. Journal of molecular and cellular cardiology 24 35041844
2018 Muscle-Specific Mis-Splicing and Heart Disease Exemplified by RBM20. Genes 23 29304022
2018 RNA-binding proteins RBM20 and PTBP1 regulate the alternative splicing of FHOD3. The international journal of biochemistry & cell biology 21 30468920
2018 Drug discovery with an RBM20 dependent titin splice reporter identifies cardenolides as lead structures to improve cardiac filling. PloS one 20 29889873
2021 RBM20 Is a Candidate Gene for Hypertrophic Cardiomyopathy. The Canadian journal of cardiology 19 34333030
2023 Loss of Cardiac Splicing Regulator RBM20 Is Associated With Early-Onset Atrial Fibrillation. JACC. Basic to translational science 18 38510713
2022 The skeletal muscle circadian clock regulates titin splicing through RBM20. eLife 18 36047761
2020 Structural basis of UCUU RNA motif recognition by splicing factor RBM20. Nucleic acids research 18 32187365
2023 Disruption of the nuclear localization signal in RBM20 is causative in dilated cardiomyopathy. JCI insight 16 37219949
2023 Sorafenib induces cardiotoxicity through RBM20-mediated alternative splicing of sarcomeric and mitochondrial genes. Pharmacological research 15 38006979
2022 I536T variant of RBM20 affects splicing of cardiac structural proteins that are causative for developing dilated cardiomyopathy. Journal of molecular medicine (Berlin, Germany) 14 36198914
2016 Emerging Role for RBM20 and its Splicing Substrates in Cardiac Function and Heart Failure. Current pharmaceutical design 13 27396593
2022 RBM20, a Therapeutic Target to Alleviate Myocardial Stiffness via Titin Isoforms Switching in HFpEF. Frontiers in cardiovascular medicine 12 35783855
2021 The ryanodine receptor stabilizer S107 ameliorates contractility of adult Rbm20 knockout rat cardiomyocytes. Physiological reports 12 34523260
2019 Angiotensin II Influences Pre-mRNA Splicing Regulation by Enhancing RBM20 Transcription Through Activation of the MAPK/ELK1 Signaling Pathway. International journal of molecular sciences 12 31614708
2022 Deep phenotyping of two preclinical mouse models and a cohort of RBM20 mutation carriers reveals no sex-dependent disease severity in RBM20 cardiomyopathy. American journal of physiology. Heart and circulatory physiology 11 36367695
2021 Malignant Arrhythmogenic Role Associated with RBM20: A Comprehensive Interpretation Focused on a Personalized Approach. Journal of personalized medicine 11 33671899
2020 Generation of pluripotent stem cell lines and CRISPR/Cas9 modified isogenic controls from a patient with dilated cardiomyopathy harboring a RBM20 p.R634W mutation. Stem cell research 11 32674065
2020 Whole-exome sequencing reveals two de novo variants in the RBM20 gene in two Chinese patients with left ventricular non-compaction cardiomyopathy. Pediatric investigation 10 32851336
2018 Phenotypic Heterogeneity within Members of a Family Carrying the Same RBM20 Mutation R634W. Cardiology 10 30557877
2021 RBM20-Associated Ventricular Arrhythmias in a Patient with Structurally Normal Heart. Genes 9 33450993
2021 Phenotype and progression among patients with dilated cardiomyopathy and RBM20 mutations. European journal of medical genetics 9 34174465
2022 Dilated cardiomyopathy caused by a pathogenic nucleotide variant in RBM20 in an Iranian family. BMC medical genomics 8 35527250
2019 Whole exome sequencing in a large pedigree with DCM identifies a novel mutation in RBM20. Acta cardiologica 8 31583969
2019 RBM20 Regulates CaV1.2 Surface Expression by Promoting Exon 9* Inclusion of CACNA1C in Neonatal Rat Cardiomyocytes. International journal of molecular sciences 8 31717392
2018 Characterization of TTN Novex Splicing Variants across Species and the Role of RBM20 in Novex-Specific Exon Splicing. Genes 8 29438341
2025 Reducing Granules Without Splicing Restoration Alleviates RBM20 Cardiomyopathy. Circulation research 7 40242865
2022 Pathogenic variant of RBM20 in a multiplex family with hypertrophic cardiomyopathy. Human genome variation 7 35181673
2022 SR Protein Kinases Regulate the Splicing of Cardiomyopathy-Relevant Genes via Phosphorylation of the RSRSP Stretch in RBM20. Genes 7 36140694
2024 Loss of endogenous estrogen alters mitochondrial metabolism and muscle clock-related protein Rbm20 in female mdx mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 6 38847487
2022 Rbm20 ablation is associated with changes in the expression of titin-interacting and metabolic proteins. Molecular omics 6 35762193
2022 Rbm20ΔRRM Mice, Expressing a Titin Isoform with Lower Stiffness, Are Protected from Mechanical Ventilation-Induced Diaphragm Weakness. International journal of molecular sciences 6 36555335
2024 Nascent transcript O-MAP reveals the molecular architecture of a single-locus subnuclear compartment built by RBM20 and the TTN RNA. bioRxiv : the preprint server for biology 4 39574693
2021 RBM20-Mediated Pre-mRNA Splicing Has Muscle-Specificity and Differential Hormonal Responses between Muscles and in Muscle Cell Cultures. International journal of molecular sciences 4 33805770
2025 Age at onset and clinical course of RBM20-mediated cardiomyopathy. Scientific reports 3 40155426
2025 The contribution of RBM20 truncating variants to human cardiomyopathy. medRxiv : the preprint server for health sciences 3 40778137
2025 Prime editing corrects the dilated cardiomyopathy causing RBM20-P633L-mutation in human cardiomyocytes. Molecular therapy. Nucleic acids 3 41210585
2023 Generation of an RBM20-mutation-associated left-ventricular non-compaction cardiomyopathy iPSC line (UMGi255-A) into a DCM genetic background to investigate monogenetic cardiomyopathies. Stem cell research 3 38141360
2021 Familial dilated cardiomyopathy with RBM20 mutation in an Indian patient: a case report. The Egyptian heart journal : (EHJ) : official bulletin of the Egyptian Society of Cardiology 3 34021826
2025 A single RBM20 missense variant is a potential contributor to dilated cardiomyopathy and/or isolated left ventricular dilatation in the Emilia Romagna region of Italy. International journal of cardiology 2 39855353
2025 Cytoplasmic mutant RBM20 causes arrhythmogenicity in murine atria. Journal of molecular and cellular cardiology 2 40480405
2024 Integrated proteomics and transcriptomics analysis reveals insights into differences in premature mortality associated with disparate pathogenic RBM20 variants. Journal of molecular and cellular cardiology 2 39490642
2021 RBM20 mutation and ventricular arrhythmias in a young patient with dilated cardiomyopathy: a case report. American journal of cardiovascular disease 2 34322310
2025 Co-existence of RBM20 and KCNQ1 gene mutations in a patient with long QT syndrome and dilated cardiomyopathy. "Which came first: Chicken or the egg?". Indian pacing and electrophysiology journal 1 40158693
2025 Q373fs variant of RBM20 affects splicing and expression of cardiac-related genes and cardiac function: human sudden death case and mouse experiments. Human molecular genetics 1 41076636
2025 Rbm20 antisense oligonucleotides alleviate diastolic dysfunction in a mouse model of cardiometabolic heart failure (HFpEF). Cardiovascular research 1 41104480
2025 Impaired retinoic acid signaling mediated Rbm20 downregulation induces aberrant splicing of CaV1.2 calcium channel: implications in myocardial hypertrophy. Journal of molecular and cellular cardiology 1 41274546
2024 Deletion of RBM20 exon 9 impairs skeletal muscle growth and satellite cell function in pigs. Biochemical and biophysical research communications 1 39632296
2026 Generation of two induced pluripotent stem cell lines from dilated cardiomyopathy patients carrying RBM20 mutations. Stem cell research 0 41570362
2026 Molecular biological effect of Rbm20 I538T knock-in mice on skeletal muscle. Legal medicine (Tokyo, Japan) 0 41795487
2026 RBM20 Truncating Variants and Human Cardiomyopathy. JAMA cardiology 0 41949880
2026 Novel Truncating Variant c.1222DupC in RBM20 Causes Cardiomyopathy Consistent With Haploinsufficiency. Circulation. Genomic and precision medicine 0 42059065
2026 CAMK2D causes heart failure in mice with RBM20 cardiomyopathy. Nature cardiovascular research 0 42082791
2026 Regulation of Tau Alternative Splicing: A Novel Role for the Ribonucleoprotein RBM20. International journal of molecular sciences 0 42123583
2025 Profiling of RBM20-Regulated CaMKIIδ Splice Variants Across the Heart, Skeletal Muscle, and Olfactory Bulbs. Genes to cells : devoted to molecular & cellular mechanisms 0 40343393
2025 Transcriptomic analysis implicates the involvement of RBM20 in Fuchs' endothelial corneal dystrophy with TCF4 repeat expansion. PloS one 0 40961119
2025 RNA binding protein RBM20 regulates turtle temperature-dependent sex determination by repressing the splicing of Wt1 KTS. Science advances 0 41237229
2023 [Research progress on the expression of the RBM20 gene in dilated cardiomyopathy]. Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics 0 37905768
2022 A quantitative RT-PCR protocol to adapt and quantify RBM20-dependent exon splicing of targets at the human locus. STAR protocols 0 35106501
2019 Megaesophagus Is a Major Pathological Condition in Rats With a Large Deletion in the Rbm20 Gene. Veterinary pathology 0 31221019

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