ArticlePLoS genetics2010
The polyproline site in hinge 2 influences the functional capacity of truncated dystrophins.
Article in PLoS genetics, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers.
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Who cites it
64 citing papers in PubMed, 85 citations in OpenAlex.
- Proteomics-based evaluation of AAV dystrophin gene therapy outcomes in mdx skeletal muscle.JCI insight · 2026Article
- From molecular correction to functional rescue: delivery, tissue state, and immunobiology as the principal constraints on dystrophin-restoring therapy in Duchenne muscular dystrophy.Frontiers in pharmacology · 2026Review
- Bidirectional role of Costameres in the pathophysiology of mdx skeletal muscles.Human molecular genetics · 2025Article
- Expression of full-length dystrophin reverses muscular dystrophy defects in young and old mdx4cv mice.The Journal of clinical investigation · 2025Article
- The road toward AAV-mediated gene therapy of Duchenne muscular dystrophy.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Incidental finding of aFrontiers in pediatrics · 2025Article
- Article
- Systemic delivery of full-length dystrophin in Duchenne muscular dystrophy mice.Nature communications · 2024Article
- Potential limitations of microdystrophin gene therapy for Duchenne muscular dystrophy.JCI insight · 2024Article
- Fine-tuning FAM161A gene augmentation therapy to restore retinal function.EMBO molecular medicine · 2024Article
- Gene therapy delivered micro-dystrophins co-localize with transgenic utrophin in dystrophic skeletal muscle fibers.Neuromuscular disorders : NMD · 2024Article
- Dystrophin- and Utrophin-Based Therapeutic Approaches for Treatment of Duchenne Muscular Dystrophy: A Comparative Review.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2024Review
- Expression and function of four AAV-based constructs for dystrophin restoration in the mdx mouse model of Duchenne muscular dystrophy.Biology open · 2023Article
- Microdystrophin Expression as a Surrogate Endpoint for Duchenne Muscular Dystrophy Clinical Trials.Human gene therapy · 2023Article
- The Implication of Hinge 1 and Hinge 4 in Micro-Dystrophin Gene Therapy for Duchenne Muscular Dystrophy.Human gene therapy · 2023Article
- Prolonged voluntary wheel running reveals unique adaptations in mdx mice treated with microdystrophin constructs ± the nNOS-binding site.Frontiers in physiology · 2023Article
- Duchenne muscular dystrophy: disease mechanism and therapeutic strategies.Frontiers in physiology · 2023Review
- Review
- Evolution and developmental functions of the dystrophin-associated protein complex: beyond the idea of a muscle-specific cell adhesion complex.Frontiers in cell and developmental biology · 2023Review
- Evaluation of the dystrophin carboxy-terminal domain for micro-dystrophin gene therapy in cardiac and skeletal muscles in the DMDGene therapy · 2022Article
4 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Mutations in dystrophin can lead to Duchenne muscular dystrophy or the more mild form of the disease, Becker muscular dystrophy. The hinge 3 region in the rod domain of dystrophin is particularly prone to deletion mutations. In-frame deletions of hinge 3 are predicted to lead to BMD, however the severity of disease can vary considerably. Here we performed extensive structure-function analyses of truncated dystrophins with modified hinges and spectrin-like repeats in mdx mice. We found that the polyproline site in hinge 2 profoundly influences the functional capacity of a microdystrophin(DeltaR4-R23/DeltaCT) with a large deletion in the hinge 3 region. Inclusion of polyproline in microdystrophin(DeltaR4-R23/DeltaCT) led to small myofibers (12% smaller than wild-type), Achilles myotendinous disruption, ringed fibers, and aberrant neuromuscular junctions in the mdx gastrocnemius muscles. Replacing hinge 2 of microdystrophin(DeltaR4-R23/DeltaCT) with hinge 3 significantly improved the functional capacity to prevent muscle degeneration, increase muscle fiber area, and maintain the junctions. We conclude that the rigid alpha-helical structure of the polyproline site significantly impairs the functional capacity of truncated dystrophins to maintain appropriate connections between the cytoskeleton and extracellular matrix.
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