Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections.
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.
Guo
Dong-Chuan
DC
Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
Pannu
Hariyadarshi
H
Tran-Fadulu
Van
V
Papke
Christina L
CL
Yu
Robert K
RK
Avidan
Nili
N
Bourgeois
Scott
S
Estrera
Anthony L
AL
Safi
Hazim J
HJ
Sparks
Elizabeth
E
Amor
David
D
Ades
Lesley
L
McConnell
Vivienne
V
Willoughby
Colin E
CE
Abuelo
Dianne
D
Willing
Marcia
M
Lewis
Richard A
RA
Kim
Dong H
DH
Scherer
Steve
S
Tung
Poyee P
PP
Ahn
Chul
C
Buja
L Maximilian
LM
Raman
C S
CS
Shete
Sanjay S
SS
Milewicz
Dianna M
DM
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
D000199:Actins