ArticleProceedings of the National Academy of Sciences of the United States of America2010
Disease-causing missense mutations in actin binding domain 1 of dystrophin induce thermodynamic instability and protein aggregation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 82 citations in OpenAlex.
- Article
- Article
- ATP-dependent thermoring basis for the heat unfolding of the first nucleotide-binding domain isolated from human CFTR.Research square · 2024Article
- Clinical and genetic interpretation of uncertain DMD missense variants: evidence from mRNA and protein studies.Orphanet journal of rare diseases · 2024Article
- Efficacy of exon-skipping therapy for DMD cardiomyopathy with mutations in actin binding domain 1.Molecular therapy. Nucleic acids · 2023Article
- Cardiomyopathy-associated variants alter the structure and function of the α-actinin-2 actin-binding domain.Biochemical and biophysical research communications · 2023Article
- Comparative mitogenomic and evolutionary analysis of Lycaenidae (Insecta: Lepidoptera): Potential association with high-altitude adaptation.Frontiers in genetics · 2023Article
- 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
- Dp71 Point Mutations Induce Protein Aggregation, Loss of Nuclear Lamina Integrity and Impaired Braf35 and Ibraf Function in Neuronal Cells.International journal of molecular sciences · 2022Article
- 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
- Data-driven modelling of mutational hotspots and in silico predictors in hypertrophic cardiomyopathy.Journal of medical genetics · 2021Article
- Ixazomib, an oral proteasome inhibitor, exhibits potential effect in dystrophin-deficient mdx mice.International journal of experimental pathology · 2021Article
- Interrogation of Dystrophin and Dystroglycan Complex Protein Turnover After Exon Skipping Therapy.Journal of neuromuscular diseases · 2021Article
- Microutrophin expression in dystrophic mice displays myofiber type differences in therapeutic effects.PLoS genetics · 2020Article
- Rapid, redox-mediated mechanical susceptibility of the cortical microtubule lattice in skeletal muscle.Redox biology · 2020Article
- Effects of Mini-Dystrophin on Dystrophin-Deficient, Human Skeletal Muscle-Derived Cells.International journal of molecular sciences · 2020Article
- EMQN best practice guidelines for genetic testing in dystrophinopathies.European journal of human genetics : EJHG · 2020Article
- PSCAN: Spatial scan tests guided by protein structures improve complex disease gene discovery and signal variant detection.Genome biology · 2020Article
- What Every Neuropathologist Needs to Know: The Muscle Biopsy.Journal of neuropathology and experimental neurology · 2020Review
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Mutations in the dystrophin gene cause Duchenne muscular dystrophy (DMD) most commonly through loss of protein expression. In a small subpopulation of patients, missense mutations can cause DMD, Becker muscular dystrophy, or X-linked cardiomyopathy. Nearly one-half of disease-causing missense mutations are located in actin-binding domain 1 (ABD1) of dystrophin. To test the hypothesis that ABD1 missense mutations cause disease by impairing actin-binding activity, we engineered the K18N, L54R, D165V, A168D, L172H, and Y231N mutations into the full-length dystrophin cDNA and characterized the biochemical properties of each mutant protein. The K18N and L54R mutations are associated with the most severe diseases in humans and each caused a small but significant 4-fold decrease in actin-binding affinity, while the affinities of the other four mutant proteins were not significantly different from WT dystrophin. More interestingly, WT dystrophin was observed to unfold in a single-step, highly cooperative manner. In contrast, all six mutant proteins were significantly more prone to thermal denaturation and aggregation. Our results suggest that missense mutations in ABD1 may all cause loss of dystrophin function via protein instability and aggregation rather than through loss of ligand binding function. However, more severe disease progressions may be due to the combinatorial effects of some mutations on both protein aggregation and impaired actin-binding activity.
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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.