ArticleThe Journal of biological chemistry2016
Severe Molecular Defects Exhibited by the R179H Mutation in Human Vascular Smooth Muscle α-Actin.
Article in The Journal of biological chemistry, 2016. 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, 26 citations in OpenAlex.
- Article
- Genomic Editing of a Pathogenic Sequence Variant inCirculation · 2025Article
- Immature Acta2Nature communications · 2025Article
- Dynamical features of smooth muscle actin pathological mutants: The arginine-257(258)-Cysteine cases.Computational and structural biotechnology journal · 2025Article
- Biochemical characterization of cardiac α-actin mutations A21V and D26N implicated in hypertrophic cardiomyopathy.Cytoskeleton (Hoboken, N.J.) · 2024Article
- Molecular mechanisms linking missense ACTG2 mutations to visceral myopathy.Science advances · 2024Article
- Case report: Multisystemic smooth muscle dysfunction syndrome: a rare genetic cause of infantile interstitial lung disease.Frontiers in pharmacology · 2024Article
- Nuclear Smooth Muscle α-actin Participates in Vascular Smooth Muscle Cell Differentiation.Nature cardiovascular research · 2023Article
- Communicating hydrocephalus and raised intracranial pressure in association with multi-systemic smooth muscle dysfunction syndrome (MSMDS).Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery · 2023Article
- Acetylation of fission yeast tropomyosin does not promote differential association with cognate formins.Cytoskeleton (Hoboken, N.J.) · 2023Article
- Enteric Neuromyopathies: Highlights on Genetic Mechanisms Underlying Chronic Intestinal Pseudo-Obstruction.Biomolecules · 2022Review
- Expanding ACTA2 genotypes with corresponding phenotypes overlapping with smooth muscle dysfunction syndrome.American journal of medical genetics. Part A · 2022Article
- Nonsurgical treatment of cerebral ischemia associated with ACTA2 cerebral arteriopathy: a case report and literature review.Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery · 2022Review
- Visceral myopathy: clinical syndromes, genetics, pathophysiology, and fall of the cytoskeleton.American journal of physiology. Gastrointestinal and liver physiology · 2021Review
- Loss of smooth muscle α-actin effects on mechanosensing and cell-matrix adhesions.Experimental biology and medicine (Maywood, N.J.) · 2020Article
- Elastic fibers and biomechanics of the aorta: Insights from mouse studies.Matrix biology : journal of the International Society for Matrix Biology · 2020Review
- Vascular disease-causing mutation, smooth muscle α-actin R258C, dominantly suppresses functions of α-actin in human patient fibroblasts.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Molecular Regulation of Arterial Aneurysms: Role of Actin Dynamics and microRNAs in Vascular Smooth Muscle.Frontiers in physiology · 2017Review
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4 authors at 1 institution in 1 country.
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Abstract
Mutations in vascular smooth muscle α-actin (SM α-actin), encoded by ACTA2, are the most common cause of familial thoracic aortic aneurysms that lead to dissection (TAAD). The R179H mutation has a poor patient prognosis and is unique in causing multisystemic smooth muscle dysfunction (Milewicz, D. M., Østergaard, J. R., Ala-Kokko, L. M., Khan, N., Grange, D. K., Mendoza-Londono, R., Bradley, T. J., Olney, A. H., Ades, L., Maher, J. F., Guo, D., Buja, L. M., Kim, D., Hyland, J. C., and Regalado, E. S. (2010) Am. J. Med. Genet. A 152A, 2437-2443). Here, we characterize this mutation in expressed human SM α-actin. R179H actin shows severe polymerization defects, with a 40-fold higher critical concentration for assembly than WT SM α-actin, driven by a high disassembly rate. The mutant filaments are more readily severed by cofilin. Both defects are attenuated by copolymerization with WT. The R179H monomer binds more tightly to profilin, and formin binding suppresses nucleation and slows polymerization rates. Linear filaments will thus not be readily formed, and cells expressing R179H actin will likely have increased levels of monomeric G-actin. The cotranscription factor myocardin-related transcription factor-A, which affects cellular phenotype, binds R179H actin with less cooperativity than WT actin. Smooth muscle myosin moves R179H filaments more slowly than WT, even when copolymerized with equimolar amounts of WT. The marked decrease in the ability to form filaments may contribute to the poor patient prognosis and explain why R179H disrupts even visceral smooth muscle cell function where the SM α-actin isoform is present in low amounts. The R179H mutation has the potential to affect actin structure and function in both the contractile domain of the cell and the more dynamic cytoskeletal pool of actin, both of which are required for contraction.
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