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 journalArticlepeer-review

631 Scopus citations


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
Issue number12
StatePublished - Dec 2007

ASJC Scopus subject areas

  • Genetics


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