Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery disease, stroke, and Moyamoya disease, along with thoracic aortic disease.
The vascular smooth muscle cell (SMC)-specific isoform of alpha-actin (ACTA2) is a major component of the contractile apparatus in SMCs located throughout the arterial system. Heterozygous ACTA2 mutations cause familial thoracic aortic aneurysms and dissections (TAAD), but only half of mutation carriers have aortic disease. Linkage analysis and association studies of individuals in 20 families with ACTA2 mutations indicate that mutation carriers can have a diversity of vascular diseases, including premature onset of coronary artery disease (CAD) and premature ischemic strokes (including Moyamoya disease [MMD]), as well as previously defined TAAD. Sequencing of DNA from patients with nonfamilial TAAD and from premature-onset CAD patients independently identified ACTA2 mutations in these patients and premature onset strokes in family members with ACTA2 mutations. Vascular pathology and analysis of explanted SMCs and myofibroblasts from patients harboring ACTA2 suggested that increased proliferation of SMCs contributed to occlusive diseases. These results indicate that heterozygous ACTA2 mutations predispose patients to a variety of diffuse and diverse vascular diseases, including TAAD, premature CAD, ischemic strokes, and MMD. These data demonstrate that diffuse vascular diseases resulting from either occluded or enlarged arteries can be caused by mutations in a single gene and have direct implications for clinical management and research on familial vascular diseases.
Guo
Dong-Chuan
DC
The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Papke
Christina L
CL
Tran-Fadulu
Van
V
Regalado
Ellen S
ES
Avidan
Nili
N
Johnson
Ralph Jay
RJ
Kim
Dong H
DH
Pannu
Hariyadarshi
H
Willing
Marcia C
MC
Sparks
Elizabeth
E
Pyeritz
Reed E
RE
Singh
Michael N
MN
Dalman
Ronald L
RL
Grotta
James C
JC
Marian
Ali J
AJ
Boerwinkle
Eric A
EA
Frazier
Lorraine Q
LQ
LeMaire
Scott A
SA
Coselli
Joseph S
JS
Estrera
Anthony L
AL
Safi
Hazim J
HJ
Veeraraghavan
Sudha
S
Muzny
Donna M
DM
Wheeler
David A
DA
Willerson
James T
JT
Yu
Robert K
RK
Shete
Sanjay S
SS
Scherer
Steven E
SE
Raman
C S
CS
Buja
L Maximilian
LM
Milewicz
Dianna M
DM
D000199:Actins / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000784:Aortic Dissection / Q000235:genetics* / Q000473:pathology; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000235:genetics* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009072:Moyamoya Disease / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D020521:Stroke / Q000235:genetics*; D055815:Young Adult
C541116:ACTA2 protein, human; D000199:Actins; D020033:Protein Isoforms