Muscle-Specific Mis-Splicing and Heart Disease Exemplified by RBM20

Rexiati, Maimaiti; Sun, Mingming; Guo, Wei

doi:10.3390/genes9010018

Cited by 30 publications

(31 citation statements)

References 77 publications

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“…Splicing regulation of RBM20 in TTN splicing has been validated only in TTN middle Ig and PEVK region (Guo et al, 2012; 2013; Li et al, 2012; 2013; Rexiati et al, 2018). It is unknown whether RBM20 also regulates the Z-band and M-band TTN splicing.…”

Section: Resultsmentioning

confidence: 99%

“…These isoforms are mainly generated from alternative splicing of the I-band exons encoding the middle immunoglobulin (Ig) region and PEVK (proline (P), glutamate (E), valine (V), and lysine (K) residues) region (Zhu et al, 2017; Greaser et al, 2008; Guo et al, 2012; 2013; Li et al, 2012; 2013). The major splicing pathways in the middle Ig domain have been well characterized (Zhu et al, 2017; Rexiati et al, 2018). Recently, a splicing factor called RNA binding motif 20 (RBM20) has been identified that regulates TTN middle Ig exon splicing (Guo et al, 2012; Li et al, 2013; Methawasin et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Z‐band and M‐band titin splicing and regulation by RNA binding motif 20 in striated muscles

Chen

Rexiati

Zhu

et al. 2018

J of Cellular Biochemistry

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Titin (TTN) has multifunctional roles in sarcomere assembly, mechanosignaling transduction, and muscle stiffness. TTN splicing generates variable protein sizes with different functions. Therefore, understanding TTN splicing is important to develop a novel treatment for TTN-based diseases. The I-band TTN splicing regulated by RNA binding motif 20 (RBM20) has been extensively studied. However, the Z- and M-band splicing and regulation remain poorly understood. Herein, we aimed to define the Z- and M-band splicing in striated muscles and determined whether RBM20 regulates the Z- and M-band splicing. We discovered four new Z-band TTN splicing variants, and one of them dominates in mouse, rat, sheep, and human hearts. But only one form can be detected in frog and chicken hearts. In skeletal muscles, three new Z repeats (Zr) were detected, and Zr4 to 6 exclusion dominates in the fast muscles, whereas Zr4 skipping dominates in the slow muscle. No developmental changes were detected in the Z-band. In the M-band, two new variants were discovered with alternative 3' splice site in exon363 (Mex5) and alternative 5' splice site in intron 362. However, only the sheep heart expresses two new variants rather than other species. Skeletal muscles express three M-band variants with altered ratios of Mex5 inclusion to Mex5 exclusion. Finally, we revealed that RBM20 does not regulate the Z- and M-band splicing in the heart, but does in skeletal muscles. Taken together, we characterized the Z- and M-band splicing and provided the first evidence of the role of RBM20 in the Z- and M-band TTN splicing.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Z‐band and M‐band titin splicing and regulation by RNA binding motif 20 in striated muscles

Chen

Rexiati

Zhu

et al. 2018

J of Cellular Biochemistry

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“…В 2009г RBM20 был впервые описан в качестве гена, связанного с развитием ДКМП [8,11,[14][15][16][17][18]. Позже было показано, что патогенные варианты этого гена связаны с развитием 2-3% случаев ДКМП во всех возрастных группах [14,15].…”

Section: Discussionunclassified

Variants of RBM20 gene in pediatric patients with dilated cardiomyopathy

et al. 2019

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Российский кардиологический журнал 2019; 24 (10) Aim. Description of three clinical cases of pediatric patients with dilated cardiomyopathy (DCMP) and an analysis of their genetic causes. Material and methods. Using the method of targeted sequencing, data were obtained on the presence of pathogenic variants of the RBM20 gene in three pediatric patients with DCMP. Results. Three cases of childhood DCMP development, associated with structural disorders in the RBM20 gene, are particularly described. It is known that RBM20 is involved in the splicing of mRNA of the TTN gene encoding the titin protein. A splicing disorder associated with pathogenic variants in the RBM20 gene can lead to a change in biomechanical and signaling processes in myocardial cells, causing pathological dilated remodeling and rhythm disorders. Conclusion. Variants in the RBM20 gene are associated with severe DCMP with a childhood debut. In some cases, the progression of RBM20-associated cardiomyopathies is associated with an infectious disease. Further study of the molecular mechanisms of the pathogenesis of DCMP associated with pathogenic variants in the TTN and RBM20 genes is extremely relevant for both clinical cardiology and fundamental medicine.

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“…Consequently, transcribed regions of interest, which are shorter than 25 nucleotides, for example some of the short exons, are not targeted. This is an important limitation in the context of DM1, as some AS events previously described in DM1, such as AS of exon 5 in cardiac troponin T (TNNT2) [22] cannot be detected. Each continuous section of DNA can be targeted by a collection of up to four probes, referred to as probeset.…”

Section: Affymetrix Genechip™ Human Exon 10 St Microarraymentioning

confidence: 99%

Towards development of a statistical framework to evaluate myotonic dystrophy type 1 mRNA biomarkers in the context of a clinical trial

et al. 2020

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Myotonic dystrophy type 1 (DM1) is a rare genetic disorder, characterised by muscular dystrophy, myotonia, and other symptoms. DM1 is caused by the expansion of a CTG repeat in the 3'-untranslated region of DMPK. Longer CTG expansions are associated with greater symptom severity and earlier age at onset. The primary mechanism of pathogenesis is thought to be mediated by a gain of function of the CUG-containing RNA, that leads to transdysregulation of RNA metabolism of many other genes. Specifically, the alternative splicing (AS) and alternative polyadenylation (APA) of many genes is known to be disrupted. In the context of clinical trials of emerging DM1 treatments, it is important to be able to objectively quantify treatment efficacy at the level of molecular biomarkers. We show how previously described candidate mRNA biomarkers can be used to model an effective reduction in CTG length, using modern high-dimensional statistics (machine learning), and a blood and muscle mRNA microarray dataset. We show how this model could be used to detect treatment effects in the context of a clinical trial.

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Muscle-Specific Mis-Splicing and Heart Disease Exemplified by RBM20

Cited by 30 publications

References 77 publications

Z‐band and M‐band titin splicing and regulation by RNA binding motif 20 in striated muscles

Z‐band and M‐band titin splicing and regulation by RNA binding motif 20 in striated muscles

Variants of RBM20 gene in pediatric patients with dilated cardiomyopathy

Towards development of a statistical framework to evaluate myotonic dystrophy type 1 mRNA biomarkers in the context of a clinical trial

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