Corpus ID: 8594082

Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections.

  title={Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections.},
  author={D. Guo and H. Pannu and V. Tran-Fadulu and Christina L. Papke and Robert K. Yu and N. Avidan and Scott Bourgeois and A. Estrera and H. Safi and E. Sparks and D. Amor and L. Ad{\`e}s and V. Mcconnell and C. Willoughby and D. Abuelo and M. Willing and R. Lewis and D. H. Kim and Steve Scherer and Poyee P. Tung and C. Ahn and L. Buja and C. Raman and S. Shete and D. Milewicz},
  journal={Nature genetics},
  volume={39 12},
The major function of vascular smooth muscle cells (SMCs) is contraction to regulate blood pressure and flow. SMC contractile force requires cyclic interactions between SMC alpha-actin (encoded by ACTA2) and the beta-myosin heavy chain (encoded by MYH11). Here we show that missense mutations in ACTA2 are responsible for 14% of inherited ascending thoracic aortic aneurysms and dissections (TAAD). Structural analyses and immunofluorescence of actin filaments in SMCs derived from individuals… Expand
Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery disease, stroke, and Moyamoya disease, along with thoracic aortic disease.
The results indicate that heterozygous ACTA2 mutations predispose patients to a variety of diffuse and diverse vascular diseases, including TAAD, premature CAD, ischemic strokes, and MMD and have direct implications for clinical management and research on familial vascular diseases. Expand
Vascular disease-causing mutation R258C in ACTA2 disrupts actin dynamics and interaction with myosin
The results align with the hypothesis that defective contractile function contributes to the pathogenesis of TAAD, and the mutant actin shows multiple defects, including impaired interaction with myosin, formation of less stable filaments, and enhanced levels of monomer. Expand
Loss of smooth muscle α-actin effects on mechanosensing and cell–matrix adhesions
The findings suggest that Acta2−/− cells are unable to generate external forces to remodel the matrix due to reduced contractility and interaction with the matrix, hence a synthetic phenotype with reduced cellular mechanosensing. Expand
Molecular Regulation of Arterial Aneurysms: Role of Actin Dynamics and microRNAs in Vascular Smooth Muscle
Current understanding about the influence of smooth muscle miRNAs and actin polymerization for the development of arterial aneurysms is summarized. Expand
Vascular disease-causing mutation, smooth muscle α-actin R258C, dominantly suppresses functions of α-actin in human patient fibroblasts
Cellular defects due to this ACTA2 mutation in both aortic smooth muscle cells and adventitial fibroblasts may contribute to development of TAAD and proliferative occlusive vascular disease. Expand
Smooth muscle hyperplasia due to loss of smooth muscle α-actin is driven by activation of focal adhesion kinase, altered p53 localization and increased levels of platelet-derived growth factor receptor-β.
Loss of α-SMA leads to SMC hyperplasia in vivo and in vitro through a mechanism involving FAK, p53 and Pdgfr-β, supporting the hypothesis that SMChyperplasia contributes to occlusive lesions in patients with ACTA2 missense mutations. Expand
Inflammation in thoracic aortic aneurysms
Treating inflammation associated with aortic aneurysms in MFS and related disorders could prove to be beneficial in limiting disease pathogenesis. Expand
From genetics to response to injury: vascular smooth muscle cells in aneurysms and dissections of the ascending aorta
Dysfunction of proteins involved in vSMC tone are interesting to study, particularly in interaction with plasma protein transport through the wall and TGF-β activation, to establish the relationship between these dysfunctions and ECM proteolysis. Expand
Risk of dissection in thoracic aneurysms associated with mutations of smooth muscle alpha-actin 2 (ACTA2)
Timely diagnosis of TAAD in the probands, genetic counselling and family screening identify predisposed relatives and prevent catastrophic aortic dissections. Expand
The defining pathology of the new clinical and histopathologic entity ACTA2-related cerebrovascular disease
Actin three-dimensional molecular modeling revealed critical positioning of R179 at the interface between the two strands of filamentous actin and destabilization of inter-strand bundling by the R179H mutation, explaining the severe associated phenotype of ACTA2-related cerebrovascular disease. Expand