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

TitleMutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections.
Publication TypeJournal Article
Year of Publication2007
AuthorsGuo, D-chuan, 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, SE, Tung, PP, Ahn, C, L Buja, M, Raman, CS, Shete, SS, Milewicz, DM
JournalNat Genet
Date Published2007 Dec
KeywordsActins, Aorta, Aortic Aneurysm, Thoracic, Aortic Dissection, Female, Genetic Predisposition to Disease, Humans, Male, Mutation, Missense, Myocytes, Smooth Muscle, Pedigree

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 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.

Alternate JournalNat Genet
PubMed ID17994018
Grant ListP50HL083794-01 / HL / NHLBI NIH HHS / United States
R01 HL62594 / HL / NHLBI NIH HHS / United States
RR024148 / RR / NCRR NIH HHS / United States

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