ArticleThe Journal of biological chemistry2012
Thoracic aortic aneurysm (TAAD)-causing mutation in actin affects formin regulation of polymerization.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 25 citations in OpenAlex.
- Structural and functional mechanisms of actin isoforms.The FEBS journal · 2025Review
- The role of vascular smooth muscle cells in the development of aortic aneurysms and dissections.European journal of clinical investigation · 2022Review
- Whole-Exome Sequencing Identified Genes Responsible for Thoracic Aortic Aneurysms and Dissections in three Chinese Families.Frontiers in genetics · 2022Article
- Molecular phenotyping and functional assessment of smooth muscle-like cells with pathogenic variants in aneurysm genes ACTA2, MYH11, SMAD3 and FBN1.Human molecular genetics · 2021Article
- 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 pathogenesis of genetic and sporadic aortic aneurysms and dissections.Current problems in surgery · 2017Review
- Molecular Regulation of Arterial Aneurysms: Role of Actin Dynamics and microRNAs in Vascular Smooth Muscle.Frontiers in physiology · 2017Review
- The defining pathology of the new clinical and histopathologic entity ACTA2-related cerebrovascular disease.Acta neuropathologica communications · 2015Article
- Vascular disease-causing mutation R258C in ACTA2 disrupts actin dynamics and interaction with myosin.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Mutant vascular actin is a TAAD misbehaving.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Aip1p dynamics are altered by the R256H mutation in actin.Journal of visualized experiments : JoVE · 2014Article
- Functional analysis of a de novo ACTB mutation in a patient with atypical Baraitser-Winter syndrome.Human mutation · 2013Article
- Importance of a Lys113-Glu195 intermonomer ionic bond in F-actin stabilization and regulation by yeast formins Bni1p and Bnr1p.The Journal of biological chemistry · 2013Article
- The prefoldin complex regulates chromatin dynamics during transcription elongation.PLoS genetics · 2013Article
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9 authors at 1 institution in 1 country.
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Abstract
More than 30 mutations in ACTA2, which encodes α-smooth muscle actin, have been identified to cause autosomal dominant thoracic aortic aneurysm and dissection. The mutation R256H is of particular interest because it also causes patent ductus arteriosus and moyamoya disease. R256H is one of the more prevalent mutations and, based on its molecular location near the strand-strand interface in the actin filament, may affect F-actin stability. To understand the molecular ramifications of the R256H mutation, we generated Saccharomyces cerevisiae yeast cells expressing only R256H yeast actin as a model system. These cells displayed abnormal cytoskeletal morphology and increased sensitivity to latrunculin A. After cable disassembly induced by transient exposure to latrunculin A, mutant cells were delayed in reestablishing the actin cytoskeleton. In vitro, mutant actin exhibited a higher than normal critical concentration and a delayed nucleation. Consequently, we investigated regulation of mutant actin by formin, a potent facilitator of nucleation and a protein needed for normal vascular smooth muscle cell development. Mutant actin polymerization was inhibited by the FH1-FH2 fragment of the yeast formin, Bni1. This fragment strongly capped the filament rather than facilitating polymerization. Interestingly, phalloidin or the presence of wild type actin reversed the strong capping behavior of Bni1. Together, the data suggest that the R256H actin mutation alters filament conformation resulting in filament instability and misregulation by formin. These biochemical effects may contribute to abnormal histology identified in diseased arterial samples from affected patients.
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