Abstract 3055: ACTA2 Mutations Cause Diverse And Diffuse Vascular Diseases, Including Aortic Aneurysms, Premature Coronary Artery Disease And Moyamoya Disease
ACTA2 encodes smooth muscle cell (SMC) α-actin, a contractile protein that is the most abundant protein in vascular SMCs. A large family (TAA327) with 10 members with autosomal dominant inheritance of thoracic aortic aneurysms leading to aortic dissection (TAAD) was characterized. Positional cloning was used to identity that a missense mutation in ACTA2, R149C, was the cause of TAAD in this family. Interestingly, all TAA327 individuals examined with ACTA2 mutations also had marked and persistent livedo reticularis (LR, a purplish rash due to occlusion of dermal capillaries) and segregation of LR alone with the ACTA2 mutation yielded a LOD of 5.85. In addition, 6 ACTA2 mutation positive TAA327 family members did not have TAAD, but rather premature CAD (age of onset < 55 years) with little to no risk factors. Direct sequencing of ACTA2 in DNA from 97 families with familial TAAD identified ACTA2 mutations in 14 families that segregated with TAAD and premature CAD in these families. No ACTA2 alterations were found in the 196 matched controls. Four families had the ACTA2 R149C mutation. Three unrelated families had mutations altering R258. Surprisingly, these families had 6 members with very premature strokes (age of onset < 30 years), with 4 of these individuals diagnosed with Moyamoya disease. Six families had unique ACTA2 mutations. The identified ACTA2 mutations segregated with TAAD (LOD score 4.14); also all individuals with premature CAD in these families carried ACTA2 mutations (combined TAAD and CAD, LOD score 8.5). Furthermore, family members with ACTA2 mutations were more likely to have premature CAD than ACTA2 negative members (p-value < 10−4). Aortic pathology from 6 patients demonstrated medial degeneration and unique finding of focal occlusion of capillaries of the vasa vasorum due to increased medial SMCs. Finally, SMCs from two ACTA2 mutation patients showed a lack of α-actin filaments, whereas control SMCs showed abundant filaments across the cells. In summary, ACTA2 mutations cause TAAD, along with occlusive disease, including premature CAD and strokes, Moyamoya disease and LR. The diversity of vascular diseases imparted by a mutation in a single gene alters our understanding and approach to identifying the genetic basis of vascular diseases.