ArticleHuman gene therapy2013
Exon skipping as a therapeutic strategy applied to an RYR1 mutation with pseudo-exon inclusion causing a severe core myopathy.
Article in Human gene therapy, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 35 citations in OpenAlex.
- Clinical and Genetic Spectrum ofMolecular syndromology · 2026Article
- Exon skipping peptide-conjugated morpholinos downregulate dynamin 2 to rescue centronuclear myopathy.Brain : a journal of neurology · 2025Article
- 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
- Treatments for RYR1-related disorders.The Cochrane database of systematic reviews · 2024Article
- Myopathic manifestations across the adult lifespan of patients with malignant hyperthermia susceptibility: a narrative review.British journal of anaesthesia · 2024Review
- Functional benefit of CRISPR-Cas9-induced allele deletion forMolecular therapy. Nucleic acids · 2024Article
- Long-term Natural History of Pediatric Dominant and RecessiveNeurology · 2023Article
- Homozygous deep intronic variant in SNX14 cause autosomal recessive Spinocerebellar ataxia 20: a case report.Frontiers in genetics · 2023Article
- Intron mutations and early transcription termination in Duchenne and Becker muscular dystrophy.Human mutation · 2022Article
- Myocardial and Arrhythmic Spectrum of Neuromuscular Disorders in Children.Biomolecules · 2021Review
- Common Pathogenic Mechanisms in Centronuclear and Myotubular Myopathies and Latest Treatment Advances.International journal of molecular sciences · 2021Review
- A recurrent COL6A1 pseudoexon insertion causes muscular dystrophy and is effectively targeted by splice-correction therapies.JCI insight · 2019Article
- 'Dusty core disease' (DuCD): expanding morphological spectrum of RYR1 recessive myopathies.Acta neuropathologica communications · 2019Article
- Ryanodine Receptor 1-Related Myopathies: Diagnostic and Therapeutic Approaches.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2018Review
- Congenital myopathies: disorders of excitation-contraction coupling and muscle contraction.Nature reviews. Neurology · 2018Review
- Review
- Review of RyR1 pathway and associated pathomechanisms.Acta neuropathologica communications · 2016Review
- In silico screening based on predictive algorithms as a design tool for exon skipping oligonucleotides in Duchenne muscular dystrophy.PloS one · 2015Article
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Authors and funding
15 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Central core disease is a myopathy often arising from mutations in the type 1 ryanodine receptor (RYR1) gene, encoding the sarcoplasmic reticulum calcium release channel RyR1. No treatment is currently available for this disease. We studied the pathological situation of a severely affected child with two recessive mutations, which resulted in a massive reduction in the amount of RyR1. The paternal mutation induced the inclusion of a new in-frame pseudo-exon in RyR1 mRNA that resulted in the insertion of additional amino acids leading to the instability of the protein. We hypothesized that skipping this additional exon would be sufficient to restore RyR1 expression and to normalize calcium releases. We therefore developed U7-AON lentiviral vectors to force exon skipping on affected primary muscle cells. The efficiency of the exon skipping was evaluated at the mRNA level, at the protein level, and at the functional level using calcium imaging. In these affected cells, we observed a decreased inclusion of the pseudo-exon, an increased RyR1 protein expression, and a restoration of calcium releases of normal amplitude either upon direct RyR1 stimulation or in response to membrane depolarization. This study is the first demonstration of the potential of exon-skipping strategy for the therapy of central core disease, from the molecular to the functional level.
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