Abnormal splicing switch of DMD’s penultimate exon compromises muscle fibre maintenance in myotonic dystrophy

Rau, Frédérique; Lainé, Jeanne; Ramanoudjame, Laetitita; Ferry, Arnaud; Arandel, Ludovic; Delalande, Olivier; Jollet, Arnaud; Dingli, Florent; Lee, Kuang‐Yung; Peccate, Cécile; Lorain, Stéphanie; Kabashi, Edor; Athanasopoulos, Takis; Koo, Taeyoung; Loew, Damarys; Swanson, Maurice S.; Rumeur, Élisabeth Le; Dickson, George; Allamand, Valérie; Marie, Joëlle; Furling, Denis

doi:10.1038/ncomms8205

Cited by 77 publications

(61 citation statements)

References 51 publications

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“…By contrast, dystrophin exon 78 is required for muscle structure maintenance in adult skeletal muscle. Its abnormal exclusion in patients suffering from myotonic dystrophy (DM) due to depletion of the MBNL1 splicing factor likely contributes to the progressive dystrophic process in DM type1 patients31. In accordance with these data, exon 78 was found to be included in about 98% of the muscular transcripts in our RNA-Seq experiments as was exon 71.…”

Section: Discussionsupporting

confidence: 85%

Targeted RNA-Seq profiling of splicing pattern in the DMD gene: exons are mostly constitutively spliced in human skeletal muscle

Bougé

Murauer

Beyne

et al. 2017

Sci Rep

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We have analysed the splicing pattern of the human Duchenne Muscular Dystrophy (DMD) NB transcript in normal skeletal muscle. To achieve depth of coverage required for the analysis of this lowly expressed gene in muscle, we designed a targeted RNA-Seq procedure that combines amplification of the full-length 11.3 kb DMD cDNA sequence and 454 sequencing technology. A high and uniform coverage of the cDNA sequence was obtained that allowed to draw up a reliable inventory of the physiological alternative splicing events in the muscular DMD transcript. In contrast to previous assumptions, we evidenced that most of the 79 DMD exons are constitutively spliced in skeletal muscle. Only a limited number of 12 alternative splicing events were identified, all present at a very low level. These include previously known exon skipping events but also newly described pseudoexon inclusions and alternative 3′ splice sites, of which one is the first functional NAGNAG splice site reported in the DMD gene. This study provides the first RNA-Seq-based reference of DMD splicing pattern in skeletal muscle and reports on an experimental procedure well suited to detect condition-specific differences in this low abundance transcript that may prove useful for diagnostic, research or RNA-based therapeutic applications.

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Section: Discussionsupporting

confidence: 85%

Targeted RNA-Seq profiling of splicing pattern in the DMD gene: exons are mostly constitutively spliced in human skeletal muscle

Bougé

Murauer

Beyne

et al. 2017

Sci Rep

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“…Most CDM cases are associated with maternal transmission of relatively large CTG exp alleles (Myring et al 1992;Tsilfidis et al 1992), and pathogenic CUG exp RNAs are expressed in a variety of prenatal/neonatal tissues (Wong and Ashizawa 1997). To date, splicing transitions for DM-relevant transcripts have been described largely as postnatal phenomena (Lin et al 2006;Brinegar et al 2017), and, while disruption of these events affects muscle function (Mankodi et al 2002) and maintenance (Rau et al 2015), misregulation of postnatal exons is not expected to prevent the morphogenesis of newborn muscle. Here, we provide evidence that major splicing transitions for exons affected in CDM occur in utero, are conserved during mouse prenatal myogenesis, and are disrupted in the absence of MBNL proteins along with coincident congenital myopathy in compound knockout mice.…”

Section: Rna Misprocessing In Cdmmentioning

confidence: 99%

Disrupted prenatal RNA processing and myogenesis in congenital myotonic dystrophy

et al. 2017

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Myotonic dystrophy type 1 (DM1) is a CTG microsatellite expansion (CTG exp ) disorder caused by expression of CUG exp RNAs. These mutant RNAs alter the activities of RNA processing factors, including MBNL proteins, leading to re-expression of fetal isoforms in adult tissues and DM1 pathology. While this pathogenesis model accounts for adult-onset disease, the molecular basis of congenital DM (CDM) is unknown. Here, we test the hypothesis that disruption of developmentally regulated RNA alternative processing pathways contributes to CDM disease. We identify prominent alternative splicing and polyadenylation abnormalities in infant CDM muscle, and, although most are also misregulated in adult-onset DM1, dysregulation is significantly more severe in CDM. Furthermore, analysis of alternative splicing during human myogenesis reveals that CDM-relevant exons undergo prenatal RNA isoform transitions and are predicted to be disrupted by CUG exp -associated mechanisms in utero. To test this possibility and the contribution of MBNLs to CDM pathogenesis, we generated mouse Mbnl double (Mbnl1; Mbnl2) and triple (Mbnl1; Mbnl2; Mbnl3) muscle-specific knockout models that recapitulate the congenital myopathy, gene expression, and spliceopathy defects characteristic of CDM. This study demonstrates that RNA misprocessing is a major pathogenic factor in CDM and provides novel mouse models to further examine roles for cotranscriptional/post-transcriptional gene regulation during development.

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“…For instance, re-expression of an embryonic dystrophin isoform due to aberrant splicing mediation of DMD exon 78 has been strongly related to the severity of DM1. Recently, it has been reported that DMD exon 78 splicing is also regulated by MBNL1 during skeletal muscle development, and mis-exclusion of exon 78 is a direct consequence of MBNL1 loss-of-function caused by CUG repeats [101]. Up to date, two antisense drugs have been approved by U.S. Food and Drug Administration (FDA) as a treatment of cytomegalovirus retinitis [102, 103] and homozygous familial hypercholesterolemia [104].…”

Section: Future Perspectivesmentioning

confidence: 99%

Pre-mRNA mis-splicing of sarcomeric genes in heart failure

Zhu

Chen

Guo

2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Pre-mRNA splicing is an important biological process that allows production of multiple proteins from a single gene in the genome, and mainly contributes to protein diversity in eukaryotic organisms. Alternative splicing is commonly governed by RNA binding proteins to meet the ever-changing demands of the cell. However, the mis-splicing may lead to human diseases. In the heart of human, mis-regulation of alternative splicing has been associated with heart failure. In this short review, we focus on alternative splicing of sarcomeric genes and review mis-splicing related heart failure with relatively well studied sarcomeric genes and splicing mechanisms with identified regulatory factors. The perspective of alternative splicing based therapeutic strategies in heart failure has also been discussed.

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Abnormal splicing switch of DMD’s penultimate exon compromises muscle fibre maintenance in myotonic dystrophy

Cited by 77 publications

References 51 publications

Targeted RNA-Seq profiling of splicing pattern in the DMD gene: exons are mostly constitutively spliced in human skeletal muscle

Targeted RNA-Seq profiling of splicing pattern in the DMD gene: exons are mostly constitutively spliced in human skeletal muscle

Disrupted prenatal RNA processing and myogenesis in congenital myotonic dystrophy

Pre-mRNA mis-splicing of sarcomeric genes in heart failure

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