ArticleProceedings of the National Academy of Sciences of the United States of America2015
Disease-proportional proteasomal degradation of missense dystrophins.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 26 citations in OpenAlex.
- Exploring extracellular vesicle MicroRNAs in Usher syndrome type 1B: Tear-Derived EVs as potential indicators of retinal health.Cellular and molecular life sciences : CMLS · 2026Article
- Review
- Expanding the Molecular Genetic Landscape of Dystrophinopathies and Associated Phenotypes.Biomedicines · 2024Article
- CRISPR-Cas9 correction in the DMD mouse model is accompanied by upregulation of Dp71f protein.Molecular therapy. Methods & clinical development · 2023Article
- Tandem duplication within the DMD gene in Labrador retrievers with a mild clinical phenotype.Neuromuscular disorders : NMD · 2022Article
- Dystrophin missense mutations alter focal adhesion tension and mechanotransduction.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Review
- Dose-Escalation Study of Systemically Delivered rAAVrh74.MHCK7.micro-dystrophin in theHuman gene therapy · 2021Article
- Ixazomib, an oral proteasome inhibitor, exhibits potential effect in dystrophin-deficient mdx mice.International journal of experimental pathology · 2021Article
- Targeting of CAT and VCAM1 as Novel Therapeutic Targets for DMD Cardiomyopathy.Frontiers in cell and developmental biology · 2021Article
- Morpholino Oligomer-Induced Dystrophin Isoforms to Map the Functional Domains in the Dystrophin Protein.Molecular therapy. Nucleic acids · 2020Article
- Pathological evaluation of rats carrying in-frame mutations in the dystrophin gene: a new model of Becker muscular dystrophy.Disease models & mechanisms · 2020Article
- The ubiquitin-proteasome system in regulation of the skeletal muscle homeostasis and atrophy: from basic science to disorders.The journal of physiological sciences : JPS · 2020Review
- Biological Activities of Gedunin-A Limonoid from the Meliaceae Family.Molecules (Basel, Switzerland) · 2020Review
- Stabilization of the cardiac sarcolemma by sarcospan rescues DMD-associated cardiomyopathy.JCI insight · 2019Article
- Immunobiology of Inherited Muscular Dystrophies.Comprehensive Physiology · 2018Review
- Dynamics of Dystrophin's Actin-Binding Domain.Biophysical journal · 2018Article
- Mouse models of two missense mutations in actin-binding domain 1 of dystrophin associated with Duchenne or Becker muscular dystrophy.Human molecular genetics · 2018Article
- Functional correction of dystrophin actin binding domain mutations by genome editing.JCI insight · 2017Article
- Identification of a novelMolecular cytogenetics · 2017Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
The 427-kDa protein dystrophin is expressed in striated muscle where it physically links the interior of muscle fibers to the extracellular matrix. A range of mutations in the DMD gene encoding dystrophin lead to a severe muscular dystrophy known as Duchenne (DMD) or a typically milder form known as Becker (BMD). Patients with nonsense mutations in dystrophin are specifically targeted by stop codon read-through drugs, whereas out-of-frame deletions and insertions are targeted by exon-skipping therapies. Both treatment strategies are currently in clinical trials. Dystrophin missense mutations, however, cause a wide range of phenotypic severity in patients. The molecular and cellular consequences of such mutations are not well understood, and there are no therapies specifically targeting this genotype. Here, we have modeled two representative missense mutations, L54R and L172H, causing DMD and BMD, respectively, in full-length dystrophin. In vitro, the mutation associated with the mild phenotype (L172H) caused a minor decrease in tertiary stability, whereas the L54R mutation associated with a severe phenotype had a more dramatic effect. When stably expressed in mammalian muscle cells, the mutations caused steady-state decreases in dystrophin protein levels inversely proportional to the tertiary stability and directly caused by proteasomal degradation. Both proteasome inhibitors and heat shock activators were able to increase mutant dystrophin to WT levels, establishing the new cell lines as a platform to screen for potential therapeutics personalized to patients with destabilized dystrophin.
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