Mutations in the gene encoding smooth muscle cell
alpha actin (ACTA2) have recently been shown to cause familial
thoracic aortic aneurysms leading to type A dissections (
TAAD) and predispose to premature
stroke and
coronary artery disease. In order to further explore the role of ACTA2 variations in the pathogenesis of
TAAD, we sequenced the coding regions of this gene in 40 unrelated German patients with
TAAD (with (n=21) or without (n=19) clinical features suggestive of
Marfan syndrome). All patients had previously tested negative for mutations in the FBN1 and
TGFBR2 genes. We identified three novel ACTA2 mutations and mapped them on a three-dimensional model of actin. Two mutations affect residues within (M49V) or adjacent to (R39C), the
DNAse-I-binding loop within subdomain 2 of
alpha actin. They were observed in families with recurrent
aortic aneurysm (R39C) or
aortic dissection (M49V). The third mutation causes an exchange in the vicinity of the
ATP-binding site (G304R) in a patient thought to have isolated
TAAD. None of the affected individuals had clinical features typical for
Marfan syndrome, and no case of premature
stroke or
coronary artery disease was reported from the affected families. In conclusion, we underscore the role of ACTA2 mutations in nonsyndromic
TAAD and suggest that ACTA2 should be included in the genes routinely investigated for syndromic and nonsyndromic
TAAD. Detailed clinical investigations of additional families are warranted to further explore the full range of phenotypic signs associated with the three novel mutations described here.