First Identification of RNA-Binding Proteins That Regulate Alternative Exons in the Dystrophin Gene

Miro, Julie; Bougé, Anne-Laure; Murauer, Eva M.; Beyne, Emmanuelle; Cunha, Dylan Da; Claustres, Mireille; Kœnig, M.; Tuffery‐Giraud, Sylvie

doi:10.3390/ijms21207803

Cited by 6 publications

(5 citation statements)

References 59 publications

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“…The data also indicate that ΔE78 is developmentally regulated. This is in agreement with previous studies reporting that ΔE78 occurs in early embryonic tissues ( 9 ), while inclusion of E78 would rather be required to maintain cell membrane integrity in adult tissues ( 27 , 50 ).…”

Section: Discussionsupporting

confidence: 93%

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Tissue- and cell-specific whole-transcriptome meta-analysis from brain and retina reveals differential expression of dystrophin complexes and new dystrophin spliced isoforms

García-Cruz

Aragón

Lourdel

et al. 2022

Human Molecular Genetics

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The large DMD gene encodes a group of dystrophin proteins in brain and retina, produced from multiple promoters and alternative splicing events. Dystrophins are core components of different scaffolding complexes in distinct cell types. Their absence may thus alter several cellular pathways, which might explain the heterogeneous genotype–phenotype relationships underlying central comorbidities in Duchenne muscular dystrophy (DMD). However, the cell-specific expression of dystrophins and associated proteins (DAPs) is still largely unknown. The present study provides a first RNA-Seq-based reference showing tissue and cell-specific differential expression of dystrophins, splice variants and DAPs in mouse brain and retina. We report that a cell type may express several dystrophin complexes, perhaps due to expression in separate cell subdomains and/or subpopulations, some of which with differential expression at different maturation stages. We also identified new splicing events in addition to the common exon-skipping events. These include a new exon within intron 51 (E51b) in frame with the flanking exons in retina, as well as inclusions of intronic sequences with stop codons leading to the presence of transcripts with elongated exons 40 and/or 41 (E40e, E41e) in both retina and brain. PCR validations revealed that the new exons may affect several dystrophins. Moreover, immunoblot experiments using a combination of specific antibodies and dystrophin-deficient mice unveiled that the transcripts with stop codons are translated into truncated proteins lacking their C-terminus, which we called N-Dp427 and N-Dp260. This study thus uncovers a range of new findings underlying the complex neurobiology of DMD.

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Section: Discussionsupporting

confidence: 93%

“…This WT sequence was detected in all tissue samples (retina, cerebellum, cortex, hippocampus, brain and skeletal muscle). The E39F-E42R primers also revealed an additional band of 267 bp (not shown), likely corresponding to the occasional skipping of exon 41 ( 27 ). The E39F and E40eR primers amplified two bands ( Fig.…”

Section: Resultsmentioning

confidence: 97%

Tissue- and cell-specific whole-transcriptome meta-analysis from brain and retina reveals differential expression of dystrophin complexes and new dystrophin spliced isoforms

García-Cruz

Aragón

Lourdel

et al. 2022

Human Molecular Genetics

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“…The DMD is a complex gene for the spliceosome machinery due to its large protein-coding sequence and intronic regions. In muscle tissue, few alternative splicing events are observed in comparison with other tissues, as a tight splicing regulation is needed in the muscle tissue to maintain dystrophin functionality 14 15. In our cohort, we detected three exon skipping events with unclear pathogenicity that commonly occur in non-muscle tissues (exon 9 skipping in P3, exon 71 skipping in P5 and P7, and exon 78 skipping in P5) 16 17.…”

Section: Discussionmentioning

confidence: 68%

“…In muscle tissue, few alternative splicing events are observed in comparison with other tissues, as a tight splicing regulation is needed in the muscle tissue to maintain dystrophin functionality. 14 15 In our cohort, we detected three exon skipping events with unclear pathogenicity that commonly occur in non-muscle tissues (exon 9 skipping in P3, exon 71 skipping in P5 and P7, and exon 78 skipping in P5). 16 17 P3, P5 and P7 present mild forms of BMD with hyperCKemia, muscle cramps or rhabdomyolisis ( table 1 ).…”

Section: Discussionmentioning

confidence: 70%

Genetic diagnosis of Duchenne and Becker muscular dystrophy through mRNA analysis: new splicing events

et al. 2022

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BackgroundUp to 7% of patients with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) remain genetically undiagnosed after routine genetic testing. These patients are thought to carry deep intronic variants, structural variants or splicing alterations not detected through multiplex ligation-dependent probe amplification or exome sequencing.MethodsRNA was extracted from seven muscle biopsy samples of patients with genetically undiagnosed DMD/BMD after routine genetic diagnosis. RT-PCR of theDMDgene was performed to detect the presence of alternative transcripts. Droplet digital PCR and whole-genome sequencing were also performed in some patients.ResultsWe identified an alteration in the mRNA level in all the patients. We detected three pseudoexons inDMDcaused by deep intronic variants, two of them not previously reported. We also identified a chromosomal rearrangement between Xp21.2 and 8p22. Furthermore, we detected three exon skipping events with unclear pathogenicity.ConclusionThese findings indicate that mRNA analysis of theDMDgene is a valuable tool to reach a precise genetic diagnosis in patients with a clinical and anatomopathological suspicion of dystrophinopathy that remain genetically undiagnosed after routine genetic testing.

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“…QKI-5 is predominantly localized in the nucleus, and its increased expression during myoblast differentiation regulates a large number of alternative splicing events involved in muscle function, among which the inclusion of muscle-specific exon from Capzb gene encoding a protein that regulates the growth of actin filament ( Hall et al, 2013 ). QKI-5 also regulates the expression of Duchenne muscular dystrophy gene ( DMD ) in skeletal muscle by promoting the inclusion of its muscle-specific exon ( Miro et al, 2020 ). Other QKI proteins may display cytoplasmic functions in fiber type specification.…”

Section: Rna-binding Proteins Involved In Skeletal Muscle Development Regeneration and Diseasementioning

confidence: 99%

RNA-Binding Proteins in the Post-transcriptional Control of Skeletal Muscle Development, Regeneration and Disease

Shi

Grifone

2021

Front. Cell Dev. Biol.

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Embryonic myogenesis is a temporally and spatially regulated process that generates skeletal muscle of the trunk and limbs. During this process, mononucleated myoblasts derived from myogenic progenitor cells within the somites undergo proliferation, migration and differentiation to elongate and fuse into multinucleated functional myofibers. Skeletal muscle is the most abundant tissue of the body and has the remarkable ability to self-repair by re-activating the myogenic program in muscle stem cells, known as satellite cells. Post-transcriptional regulation of gene expression mediated by RNA-binding proteins is critically required for muscle development during embryogenesis and for muscle homeostasis in the adult. Differential subcellular localization and activity of RNA-binding proteins orchestrates target gene expression at multiple levels to regulate different steps of myogenesis. Dysfunctions of these post-transcriptional regulators impair muscle development and homeostasis, but also cause defects in motor neurons or the neuromuscular junction, resulting in muscle degeneration and neuromuscular disease. Many RNA-binding proteins, such as members of the muscle blind-like (MBNL) and CUG-BP and ETR-3-like factors (CELF) families, display both overlapping and distinct targets in muscle cells. Thus they function either cooperatively or antagonistically to coordinate myoblast proliferation and differentiation. Evidence is accumulating that the dynamic interplay of their regulatory activity may control the progression of myogenic program as well as stem cell quiescence and activation. Moreover, the role of RNA-binding proteins that regulate post-transcriptional modification in the myogenic program is far less understood as compared with transcription factors involved in myogenic specification and differentiation. Here we review past achievements and recent advances in understanding the functions of RNA-binding proteins during skeletal muscle development, regeneration and disease, with the aim to identify the fundamental questions that are still open for further investigations.

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First Identification of RNA-Binding Proteins That Regulate Alternative Exons in the Dystrophin Gene

Cited by 6 publications

References 59 publications

Tissue- and cell-specific whole-transcriptome meta-analysis from brain and retina reveals differential expression of dystrophin complexes and new dystrophin spliced isoforms

Tissue- and cell-specific whole-transcriptome meta-analysis from brain and retina reveals differential expression of dystrophin complexes and new dystrophin spliced isoforms

Genetic diagnosis of Duchenne and Becker muscular dystrophy through mRNA analysis: new splicing events

RNA-Binding Proteins in the Post-transcriptional Control of Skeletal Muscle Development, Regeneration and Disease

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