ArticleBiochimica et biophysica acta2016
Myopathy-inducing mutation H40Y in ACTA1 hampers actin filament structure and function.
Article in Biochimica et biophysica acta, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 21 citations in OpenAlex.
- Pathogenic TNNT1 variants are associated with aberrant thin filament compliance and myofibre hyper-contractility.The Journal of physiology · 2025Article
- Morphological and functional alterations of neuromuscular synapses in a mouse model of ACTA1 congenital myopathy.Human molecular genetics · 2024Article
- Different Mouse Models of Nemaline Myopathy Harboring Acta1 Mutations Display Differing Abnormalities Related to Mitochondrial Biology.The American journal of pathology · 2023Article
- Variants inHGG advances · 2023Article
- ACTA1 H40Y mutant iPSC-derived skeletal myocytes display mitochondrial defects in an in vitro model of nemaline myopathy.Experimental cell research · 2023Article
- Variants inmedRxiv : the preprint server for health sciences · 2023Article
- Acute and chronic tirasemtiv treatment improves in vivo and in vitro muscle performance in actin-based nemaline myopathy mice.Human molecular genetics · 2021Article
- Identification of Chimeric RNAs in Pig Skeletal Muscle and Transcriptomic Analysis of Chimeric RNA TNNI2-ACTA1 V1.Frontiers in veterinary science · 2021Article
- Actin Mutations and Their Role in Disease.International journal of molecular sciences · 2020Review
- Impairments in contractility and cytoskeletal organisation cause nuclear defects in nemaline myopathy.Acta neuropathologica · 2019Article
- Nemaline myopathies: a current view.Journal of muscle research and cell motility · 2019Review
- Nebulin stiffens the thin filament and augments cross-bridge interaction in skeletal muscle.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Molecular Consequences of the Myopathy-Related D286G Mutation on Actin Function.Frontiers in physiology · 2018Article
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Authors and funding
6 authors at 5 institutions in 4 countries.
Funding
Abstract
In humans, more than 200 missense mutations have been identified in the ACTA1 gene. The exact molecular mechanisms by which, these particular mutations become toxic and lead to muscle weakness and myopathies remain obscure. To address this, here, we performed a molecular dynamics simulation, and we used a broad range of biophysical assays to determine how the lethal and myopathy-related H40Y amino acid substitution in actin affects the structure, stability, and function of this protein. Interestingly, our results showed that H40Y severely disrupts the DNase I-binding-loop structure and actin filaments. In addition, we observed that normal and mutant actin monomers are likely to form distinctive homopolymers, with mutant filaments being very stiff, and not supporting proper myosin binding. These phenomena underlie the toxicity of H40Y and may be considered as important triggering factors for the contractile dysfunction, muscle weakness and disease phenotype seen in patients.
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