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

AbstractRBM20 is one of the genes predisposing to dilated cardiomyopathy (DCM). Variants in the RS domain have been reported in many DCM patients, but the pathogenicity of variants within the RNA-recognition motif remains unknown. Two human patients with the I536T-RBM20 variant without an apparent DCM phenotype were identified in sudden death cohorts. A splicing reporter assay was performed, and an I538T knock-in mouse model (Rbm20I538T) was generated to determine the significance of this variant. The reporter assay demonstrated that the human I536T variant affected theTTN splicing pattern compared to wild-type. In the mouse experiments,Rbm20I538T mice showed different splicing patterns inTtn,Ldb3,Camk2d, andRyr2. The expressions ofCasq1,Mybpc2, andMyot were upregulated inRbm20I538T mice, butRbm20I538T mice showed neither DCM nor cardiac dysfunction on histopathological examination and ultrasound echocardiography. The I536T-RBM20 (I538T-Rbm20) variant changes gene splicing and affects gene expression, but the splicing and expression changes inTtn and Ca handling genes such asCasq1,Camk2d, andRyr2 do not cause DCM morphology in the mouse model.Key messages• Two human patients with the I536T-RBM20 variant without a DCM phenotype were identified.• A splicing reporter assay demonstrated that the variant affected theTTN splicing.• Rbm20I538T mice showed neither DCM nor cardiac dysfunction.• Rbm20I538T mice showed different splicing patterns and the gene expressions.
Source: Journal of Molecular Medicine - Category: Molecular Biology Source Type: research