title: Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections.
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 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.
authors.affiliation: Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
authors.forename: Dong-Chuan
authors.initials: DC
authors.lastname: Guo
authors.forename: Hariyadarshi
authors.initials: H
authors.lastname: Pannu
authors.forename: Van
authors.initials: V
authors.lastname: Tran-Fadulu
authors.forename: Christina L
authors.initials: CL
authors.lastname: Papke
authors.forename: Robert K
authors.initials: RK
authors.lastname: Yu
authors.forename: Nili
authors.initials: N
authors.lastname: Avidan
authors.forename: Scott
authors.initials: S
authors.lastname: Bourgeois
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Estrera
authors.forename: Hazim J
authors.initials: HJ
authors.lastname: Safi
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sparks
authors.forename: David
authors.initials: D
authors.lastname: Amor
authors.forename: Lesley
authors.initials: L
authors.lastname: Ades
authors.forename: Vivienne
authors.initials: V
authors.lastname: McConnell
authors.forename: Colin E
authors.initials: CE
authors.lastname: Willoughby
authors.forename: Dianne
authors.initials: D
authors.lastname: Abuelo
authors.forename: Marcia
authors.initials: M
authors.lastname: Willing
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lewis
authors.forename: Dong H
authors.initials: DH
authors.lastname: Kim
authors.forename: Steve
authors.initials: S
authors.lastname: Scherer
authors.forename: Poyee P
authors.initials: PP
authors.lastname: Tung
authors.forename: Chul
authors.initials: C
authors.lastname: Ahn
authors.forename: L Maximilian
authors.initials: LM
authors.lastname: Buja
authors.forename: C S
authors.initials: CS
authors.lastname: Raman
authors.forename: Sanjay S
authors.initials: SS
authors.lastname: Shete
authors.forename: Dianna M
authors.initials: DM
authors.lastname: Milewicz
mesh_terms: D000199:Actins / Q000235:genetics*; D000784:Aortic Dissection / Q000235:genetics*; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D010375:Pedigree
chemical_list: D000199:Actins