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

Dong Chuan Guo, Hariyadarshi Pannu, Van Tran-Fadulu, Christina L. Papke, Robert K. Yu, Nili Avidan, Scott Bourgeois, Anthony L. Estrera, Hazim J. Safi, Elizabeth Sparks, David Amor, Lesley Ades, Vivienne McConnell, Colin E. Willoughby, Dianne Abuelo, Marcia Willing, Richard A. Lewis, Dong H. Kim, Steve Scherer, Poyee P. TungChul Ahn, L. Maximilian Buja, C. S. Raman, Sanjay S. Shete, Dianna M. Milewicz

Research output: Contribution to journalArticle

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Abstract

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 α-actin (encoded by ACTA2) and the β-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 heterozygous for ACTA2 mutations illustrate that these mutations interfere with actin filament assembly and are predicted to decrease SMC contraction. Aortic tissues from affected individuals showed aortic medial degeneration, focal areas of medial SMC hyperplasia and disarray, and stenotic arteries in the vasa vasorum due to medial SMC proliferation. These data, along with the previously reported MYH11 mutations causing familial TAAD, indicate the importance of SMC contraction in maintaining the structural integrity of the ascending aorta.

Original languageEnglish (US)
Pages (from-to)1488-1493
Number of pages6
JournalNature Genetics
Volume39
Issue number12
DOIs
StatePublished - Dec 2007

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Thoracic Aortic Aneurysm
Smooth Muscle Myocytes
Smooth Muscle
Dissection
Actins
Mutation
Muscle Contraction
Actin Cytoskeleton
Vasa Vasorum
Myosin Heavy Chains
Missense Mutation
Vascular Smooth Muscle
Hyperplasia
Fluorescent Antibody Technique
Aorta
Arteries
Cell Proliferation
Blood Pressure

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Guo, D. C., Pannu, H., Tran-Fadulu, V., Papke, C. L., Yu, R. K., Avidan, N., ... Milewicz, D. M. (2007). Mutations in smooth muscle α-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nature Genetics, 39(12), 1488-1493. https://doi.org/10.1038/ng.2007.6

Mutations in smooth muscle α-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. / Guo, Dong Chuan; Pannu, Hariyadarshi; Tran-Fadulu, Van; Papke, Christina L.; Yu, Robert K.; Avidan, Nili; Bourgeois, Scott; Estrera, Anthony L.; Safi, Hazim J.; Sparks, Elizabeth; Amor, David; Ades, Lesley; McConnell, Vivienne; Willoughby, Colin E.; Abuelo, Dianne; Willing, Marcia; Lewis, Richard A.; Kim, Dong H.; Scherer, Steve; Tung, Poyee P.; Ahn, Chul; Buja, L. Maximilian; Raman, C. S.; Shete, Sanjay S.; Milewicz, Dianna M.

In: Nature Genetics, Vol. 39, No. 12, 12.2007, p. 1488-1493.

Research output: Contribution to journalArticle

Guo, DC, Pannu, H, Tran-Fadulu, V, Papke, CL, Yu, RK, Avidan, N, Bourgeois, S, Estrera, AL, Safi, HJ, Sparks, E, Amor, D, Ades, L, McConnell, V, Willoughby, CE, Abuelo, D, Willing, M, Lewis, RA, Kim, DH, Scherer, S, Tung, PP, Ahn, C, Buja, LM, Raman, CS, Shete, SS & Milewicz, DM 2007, 'Mutations in smooth muscle α-actin (ACTA2) lead to thoracic aortic aneurysms and dissections', Nature Genetics, vol. 39, no. 12, pp. 1488-1493. https://doi.org/10.1038/ng.2007.6
Guo DC, Pannu H, Tran-Fadulu V, Papke CL, Yu RK, Avidan N et al. Mutations in smooth muscle α-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nature Genetics. 2007 Dec;39(12):1488-1493. https://doi.org/10.1038/ng.2007.6
Guo, Dong Chuan ; Pannu, Hariyadarshi ; Tran-Fadulu, Van ; Papke, Christina L. ; Yu, Robert K. ; Avidan, Nili ; Bourgeois, Scott ; Estrera, Anthony L. ; Safi, Hazim J. ; Sparks, Elizabeth ; Amor, David ; Ades, Lesley ; McConnell, Vivienne ; Willoughby, Colin E. ; Abuelo, Dianne ; Willing, Marcia ; Lewis, Richard A. ; Kim, Dong H. ; Scherer, Steve ; Tung, Poyee P. ; Ahn, Chul ; Buja, L. Maximilian ; Raman, C. S. ; Shete, Sanjay S. ; Milewicz, Dianna M. / Mutations in smooth muscle α-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. In: Nature Genetics. 2007 ; Vol. 39, No. 12. pp. 1488-1493.
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