Three novel mutations in the ACTA2 gene in German patients with thoracic aortic aneurysms and dissections

Abstract

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 (n¼21) or without (n¼19) 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.

Gene panel sequencing in heritable thoracic aortic disorders and related entities – results of comprehensive testing in a cohort of 264 patients

“…(Arg287Trp)S H-TAD2632c.887 T > C*p. (Leu296Pro)S H-TAD2720c.1155-2A > G*/S H-TAD ACTA2 2861c.115C > T [19,38]p. (Arg39Cys)NS H-TAD2917c.455C > T [18]p.…”

“…(Arg149Cys)NS H-TAD3059c.772C > T [25]p. (Arg258Cys)NS H-TAD3132c.910G > A [38]p. (Gly304Ser)NS H-TAD COL3A1 3240c.3410G > A [39]p.…”

Genetic Dissection of Marfan Syndrome and Related Connective Tissue Disorders: An Update 2012

“…Interestingly, ACTA2 mutations seem to increase risk not only for aneurysms/dissections, but also for occlusive arterial disease including premature stroke, premature coronary artery disease and Moya-Moya disease [Guo et al, 2009]. While MYH11 mutations appear to be rare (only 5 mutations reported so far) and have been exclusively described in association with patent ductus arteriosus, ACTA2 mutations were found to be responsible for approximately 14-21% of fTAAD and are believed to interfere with the normal assembly of actin filaments [Hoffjan et al, 2011]. Recently, mutations in the gene encoding the kinase that controls SMC contractile function (myosin light chain kinase (MYLK) on chromosome 3q21) were also shown to cause familial aortic dissections [Wang et al, 2010].…”

Thoracic Aortic Aneurysm (TAAD)-causing Mutation in Actin Affects Formin Regulation of Polymerization

“…Mutations in ␣-smooth muscle actin, encoded by ACTA2, are the most common genetic cause of familial thoracic aortic aneurysm and dissection (TAAD) 3 (1). More than 30 ACTA2 mutations have been identified to cause this potentially fatal disorder and are now known to differentially cause additional vascular diseases, including coronary artery disease, occlusive stroke, and patent ductus arteriosus (2-7).…”