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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE308500 | GEO | 2026/03/18

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.

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

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