ArticleAnnals of clinical and translational neurology2014
A novel dysferlin mutant pseudoexon bypassed with antisense oligonucleotides.
Article in Annals of clinical and translational neurology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
21 citing papers in PubMed, 28 citations in OpenAlex.
- Peptide-phosphorodiamidate morpholino oligomer therapy for dysferlinopathy induces pseudoexon skipping and restoration of functional protein.JCI insight · 2026Article
- Splice-modulating antisense oligonucleotides targeting a pathogenic intronic variant in adult polyglucosan body disease correct mis-splicing and restore enzyme activity in patient cells.Nucleic acids research · 2025Article
- Antisense oligonucleotide-mediated exon 27 skipping restores dysferlin function in dysferlinopathy patient-derived muscle cells.Molecular therapy. Nucleic acids · 2025Article
- Review
- Tips to Design Effective Splice-Switching Antisense Oligonucleotides for Exon Skipping and Exon Inclusion.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Limb Girdle Muscular Dystrophy Type 2B (LGMD2B): Diagnosis and Therapeutic Possibilities.International journal of molecular sciences · 2024Review
- An in-frame pseudoexon activation caused by a novel deep-intronic variant in the dysferlin gene.Annals of clinical and translational neurology · 2023Article
- Morpholino-Mediated Exons 28-29 Skipping of Dysferlin and Characterization of Multiexon-skipped Dysferlin using RT-PCR, Immunoblotting, and Membrane Wounding Assay.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Intron mutations and early transcription termination in Duchenne and Becker muscular dystrophy.Human mutation · 2022Article
- Integrated Genome and Transcriptome Sequencing to Solve a Neuromuscular Puzzle: Miyoshi Muscular Dystrophy and Early Onset Primary Dystonia in Siblings of the Same Family.Frontiers in genetics · 2021Article
- Analysis of Pathogenic Pseudoexons Reveals Novel Mechanisms Driving Cryptic Splicing.Frontiers in genetics · 2021Article
- Correction of pseudoexon splicing caused by a novel intronic dysferlin mutation.Annals of clinical and translational neurology · 2019Article
- A recurrent COL6A1 pseudoexon insertion causes muscular dystrophy and is effectively targeted by splice-correction therapies.JCI insight · 2019Article
- Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients.Annals of clinical and translational neurology · 2018Article
- Deep intronic mutations and human disease.Human genetics · 2017Review
- Hip region muscular dystrophy and emergence of motor deficits in dysferlin-deficient Bla/J mice.Physiological reports · 2017Article
- Full-length Dysferlin Transfer by the Hyperactive Sleeping Beauty Transposase Restores Dysferlin-deficient Muscle.Molecular therapy. Nucleic acids · 2016Article
- Dysferlinopathy Fibroblasts Are Defective in Plasma Membrane Repair.PLoS currents · 2015Article
- Exon 32 Skipping of Dysferlin Rescues Membrane Repair in Patients' Cells.Journal of neuromuscular diseases · 2015Article
- Reply to comment on: A novel dysferlin mutant pseudoexon bypassed with antisense oligonucleotides.Annals of clinical and translational neurology · 2015Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
objectiveMutations in dysferlin (DYSF), a Ca(2+)-sensitive ferlin family protein important for membrane repair, vesicle trafficking, and T-tubule function, cause Miyoshi myopathy, limb-girdle muscular dystrophy type 2B, and distal myopathy. More than 330 pathogenic DYSF mutations have been identified within exons or near exon-intron junctions. In ~17% of patients who lack normal DYSF, only a single disease-causing mutation has been identified. We studied one family with one known mutant allele to identify both the second underlying genetic defect and potential therapeutic approaches.
methodsWe sequenced the full DYSF cDNA and investigated antisense oligonucleotides (AONs) as a tool to modify splicing of the mRNA transcripts in order to process out mutant sequences.
resultsWe identified a novel pseudoexon between exons 44 and 45, (pseudoexon 44.1, PE44.1), which inserts an additional 177 nucleotides into the mRNA and 59 amino acids within the conserved C2F domain of the DYSF protein. Two unrelated dysferlinopathy patients were also found to carry this mutation. Using AONs targeting PE44.1, we blocked the abnormal splicing event, yielding normal, full-length DYSF mRNA, and increased DYSF protein expression.
interpretationThis is the first report of a deep intronic mutation in DYSF that alters mRNA splicing to include a mutant peptide fragment within a key DYSF domain. We report that AON-mediated exon-skipping restores production of normal, full-length DYSF in patients' cells in vitro, offering hope that this approach will be therapeutic in this genetic context, and providing a foundation for AON therapeutics targeting other pathogenic DYSF alleles.
Identifiers
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.