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Patients based and Knock-in-mouse analysis reveals I536T variant of RBM20 is not contributory to myopathy

ABSTRACT: Introduction: RBM20 regulates pre-mRNA splicing, and its mutations cause dilated cardiomyopathy by disrupting cardiac RNA splicing, particularly of the TTN gene. While RBM20 is known to affect TTN splicing in the heart, its role in skeletal muscle remains unclear. This study investigated the effects of an RBM20 variant using an Rbm20 I538T knock-in mouse model, performing pathological and RNA-seq analyses to assess its impact on skeletal muscle. Methods: We used Rbm20 I538T knock-in mouse and performed pathological and RNA-seq analyses to evaluate the effect of the variant on skeletal muscle. Results and Discussion: Histopathological examination revealed no skeletal muscle abnormalities in any genotype. Although potential splicing effects on Ttn and Ldb3 were considered, no abnormal splicing was detected. Differentially expressed gene analysis showed no differences among genotypes. Therefore, we conclude that the Rbm20 I538T variant does not affect the splicing of skeletal structural proteins or lead to a skeletal muscle phenotype.

ORGANISM(S): Mus musculus

PROVIDER: GSE255940 | GEO | 2026/03/02

REPOSITORIES: GEO

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I536T variant of RBM20 affects splicing of cardiac structural proteins that are causative for developing dilated cardiomyopathy

Project description:Background: RBM20 gene is one of the genetic predispositions for dilated cardiomyopathy (DCM). Variants in RS domain has been reported in many DCM patients, while the pathogenicity of variants within the RNA-recognition motif remains unknown. Methods and results: We detected two human patients of I536T-RBM20 variant without DCM phenotype in sudden death cohorts. We performed splicing reporter assay and generated I538T knock-in (KI) mouse model (Rbm20I538T) in order to reveal the significance of this variant. The reporter assay revealed that human I536T variant affected TTN splicing pattern compared to wild-type. In the mouse experiments, Rbm20I538T mice presented a different splicing pattern in Ttn, Ldb3, Camk2d and Ryr2. The expression of Casq1, Mybpc2 and Myot were upregulated in Rbm20I538T mice. Whereas, Rbm20I538T mice did show neither DCM nor cardiac dysfunction by histopathological examination and ultrasound echocardiography. Conclusion: I536T-RBM20 (I538T-Rbm20) variant does not cause DCM phenotype, but changes the gene splicing and expression effect. The splicing and expression changes in Ttn and Ca handling genes such as Casq1, Camk2d and Ryr2 may be contributory to sudden arrhythmogenic death.

2022-10-05 | GSE201018 | GEO

Q373fs variant of RBM20 affects splicing of cardiac genes that are causative for sudden death; Human sudden death case and animal experiment

Project description:RBM20 is one of the genes predisposing to dilated cardiomyopathy (DCM). Variants in the RS domain and the RNA-recognition motif have been well studied, but the pathogenicity of variants outside the hotspot remains unknown. A human patient with the Q373fs-RBM20 variant without a typical DCM phenotype was identified in sudden death cohorts. In the mouse experiments, RNA seq analysis revealed that Q374fs-Rbm20 mice showed some different splicing patterns in such as Ttn, Ldb3, Camk2d,Obscn, and Ryr2. The expressions of Casq1, Mybpc2, and Myot were also upregulated in Q374fs-Rbm20 mice. The pathway analysis indicated the involvement of some of the 1770 differentially expressed genes in Cytoplasmic ribosomal proteins Calcium regulation in cardiac cells and Striated muscle contraction. Cardiac dysfunction such as cardiac dilation and extended duration of QRS and QTc were observed by ultrasound echocardiography and Electro-cardiogram. The Q373fs-RBM20 (Q374fs-Rbm20) variant changes gene splicing and affects gene expression of sarcomere structural genes and Ca handling genes and presented cardiac dysfunction, suggesting that Q373fs-RBM20 human patient may cause arrhythmogenic sudden death.

2025-10-13 | GSE292651 | GEO

Effect of CAMK2D inhibition in RBM20 loss of function mouse models

Project description:Mutations in RBM20, a splicing factor that targets multiple pivotal cardiac genes including TTN and CAMK2D, cause a clinically aggressive form of dilated cardiomyopathy (DCM) with a high risk of malignant ventricular arrhythmias. We hypothesized that the RBM20 target CAMK2D contributes critically to RBM20 cardiomyopathy. Here, we sequenced the hearts of Rbm20/Camk2d double knockout mice, as well as the hearts of Rbm20-R636Q knock-in mice treated with the CAMK2 inhibitor Hesperadin.

2025-12-01 | GSE311410 | GEO

A novel truncating variant c.1222dupC in RBM20 causes cardiomyopathy through haplo-insufficiency.

Project description:RBM20 is a cardiac splicing factor responsible for splicing of several cardiac genes such as TTN, TRDN, RyR2, PDLIM1, and CAMK2D. Mutations in RBM20 are a major cause of familial dilated cardiomyopathy (DCM), and lead to missplicing of RBM20 target genes. Here, we describe a novel pathogenic truncating mutation, RBM20 c.1222dupC, identified in a patient with mitral valve prolapse and late onset familial DCM. This mutation introduces a premature termination codon and generates a truncated protein of ~55 kDa in vitro. Splicing assays demonstrated complete loss of activity and no dominant-negative effect on WT RBM20. Overexpression in NRCMs revealed that the truncated protein localized to both cytoplasm and nucleus, partially co-localizing with WT RBM20, despite lacking the RS and RRM domains. To model the patient’s condition, we generated heterozygous c.1222dupC iPSC-derived cardiomyocytes. Western blot analysis of endogenous RBM20 revealed a strong reduction in RBM20 protein level. RT-PCR revealed splicing defects in canonical RBM20 targets, and RNA-sequencing identified widespread splicing abnormalities, including in established RBM20 targets (TTN, RyR2, CAMK2D, and CACNA1G). Together, these findings establish RBM20 c.1222dupC as a pathogenic truncating variant that causes DCM primarily through haploinsufficiency.

2026-03-18 | GSE308500 | GEO

RBM20 orchestrates cardiac pre-mRNA

Project description:The RNA-binding protein RBM20 has been implicated in dilated cardiomyopathy (DCM), a major cause of chronic heart failure. To determine how RBM20 regulates alternative splicing, we combined transcriptome-wide CLIP-seq, RNA-seq, and quantitative proteomics in cell culture, rat, and human hearts. Our analyses revealed a distinct RBM20 RNA-recognition element in predominantly intronic binding sites and linked repression of exon splicing with RBM20-binding near 3prime- and 5prime-splice sites. Our proteomic data show RBM20 interaction with U1- and U2-snRNPs and suggests splicing repression through spliceosome stalling at complex A. Among direct RBM20 targets are several genes involved in DCM as well as new genes not previously associated with the disease process. In human failing hearts, we demonstrate that reduced expression levels of RBM20 affect alternative splicing of several direct targets, indicating that differences in RBM20 gene expression may affect cardiac function. These findings reveal a new mechanism to understand the pathogenesis of human heart failure. The provided data files for RNA-seq contain information for reads that map to human RBM20 only.

2014-11-11 | E-MTAB-2572 | biostudies-arrayexpress

Deletion of the RS domain in RBM20 leads to dilated cardiomyopathy

Project description:Human patients carrying genetic mutations in RBM20 develop a clinically aggressive dilated cardiomyopathy (DCM) characterized by early onset heart failure, high mortality, and sudden death, which is recapitulated in animal models. RBM20 has two primary domains, an RNA recognition motif (RRM) that binds RNA and an arginine/serine (RS)-rich domain that mediates spliceosome assembly and nuclear localization. Reported data showed that mutations in the RS domain lead to severe DCM. Loss of the RRM domain in RBM20 has been shown to disrupt the splicing of RBM20 target transcripts but does not lead to DCM. The objectives of the present study were to determine the functional role of the RS domain in DCM and examine the mechanisms. Mice expressing RBM20 lacking the RS domain (Rbm20ΔRS) were generated using CRISPR/Cas9 technology. Male and female Rbm20ΔRS mice developed a DCM-like phenotype characterized by ventricular dilation and impaired systolic function, that is more severe in females. Splicing of RBM20 target genes, including Ttn, was disrupted in both Rbm20ΔRS and Rbm20ΔRRM mice. However, RBM20 was mis-localized to the sarcoplasm only in the hearts of Rbm20ΔRS mice, indicating that mis-localization of RBM20 rather than disrupted splicing is key in DCM pathogenesis.

2023-01-02 | GSE212799 | GEO

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

Project description: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 variants retain their splice regulatory activity, which reveals that aberrant cellular localization drives the pathological phenotype. A genome-wide CRISPR knock-out 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, disrupted by pathogenic variants. Re-localization 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.

2023-06-19 | PXD038790 | Pride

Heart RNA-seq of therapeutic RBM20 antisense oligonucleotide (ASO) treatment in a mouse model of heart failure with preserved ejection fraction (HFpEF)

Project description:We report the heart RNA-sequencing of control animals and animals of a mouse model of heart failure treated or not with RBM20 antisense oligonucleotide. This study aims to investigate the therapeutic effect of antisense oligonucleotide (ASO)-mediated downregulation of the cardiac splice factor RBM20 in a mouse model of heart failure with preserved ejection fraction. 8-week old wild type and titin N2B KO mice with increased wall stiffness were subcutaneously injected with 50 mg/kg/week RBM20 ASO for 8 weeks. RNA from 4 left ventricles per group were isolated using TRIzol followed by a clean-up with the QIAGEN RNA micro kit. The cDNA libraries were generated using the Illumina TruSeq Stranded mRNA LT Sample Prep Kit and 2x150 paired end sequenced on HiSeq4000. The RNA-Sequencing analysis confirms that RBM20 ASO treatment increased the expression of compliant titin isoforms and improved impaired ventricular filling and cardiac function. RNA-seq confirmed RBM20 dependent isoform changes of known targets such as Titin, Ldb3, Camk2d, and Ank3, and served as a sensitive indicator of potential side effects, largely limited to genes related to the immune response.

2021-12-06 | E-MTAB-9361 | biostudies-arrayexpress

Nascent transcript O-MAP reveals the molecular architecture a single-locus subnuclear compartment built by RBM20 and the TTN noncoding RNA

Project description:We here adapt Oligonucleotide-mediated proximity-interactome mapping (O-MAP), a novel RNA-targeted microenvironment-mapping method, to biochemically characterize the molecular neighborhoods near individual genomic loci. By targeting O-MAP to introns within the TTN pre-mRNA, we have systematically mapped the chromatin loci, RNAs, and proteins within a cardiomyocyte-specific "RNA factory" nucleated on these TTN-derived noncoding transcripts. This revealed an unanticipated compartmental architecture that organizes trans-chromosomal domains into a hub of transcriptionally silenced chromatin, and which recruits dozens of unique RNA-binding and chromatin-scaffolding factors, including QKI and SAFB, along with their target transcripts. Loss of the cardiac-specific splicing factor RBM20, a master regulator of TTN splicing, remodels nearly every facet of factor architecture, suggesting new mechanisms in RBM20-driven dilated cardiomyopathy. This establishes O-MAP as a pioneering method for probing single-locus, microcompartment-level interactions that are opaque to conventional tools, and suggests new mechanisms by which coding genes can "moonlight" as nuclear-architectural noncoding RNAs.

2024-10-08 | MSV000096046 | MassIVE

AAV9-mediated TNPO3 overexpression in the heart rescues RBM20 cardiomyopathy in mice

Project description:The RBM20 gene encodes for an alternative splicing regulator which, when mutated, can cause an aggressive form of DCM. The majority of RBM20 mutations identified in patients are found in the RS-domain, and lead to cytoplasmic mislocalization of the protein. In our previous work (Kornienko et al., Nat Commun, 2023), we identified TNPO3 as a direct nuclear importer of RBM20, and showed that restoring nuclear localization of mislocalizing variants rescues splicing dysfunction in iPSC-CMs. Here, we used our two recently published mouse models with patient-relevant RBM20 variants (Grosch et al., Nat Commun, 2023) to test whether nuclear relocalization could restore the alternative splicing and cardiac dysfunction in vivo. We used AAV9 vectors to overexpress TNPO3 in murine hearts and thereby facilitate nuclear import of RBM20 variants. We show that TNPO3 overexpression could rescue ejection fraction, cardiac volume, and alternative splicing, without having any detectable adverse effects on wild type animals. These results provide the first in vivo evidence that restoring RBM20 localization can significantly improve cardiac function and correct for splicing errors.

2025-09-10 | GSE284034 | GEO

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