Mutant vascular actin is a TAAD misbehaving

Actin plays a number of important roles in mammalian cells. Mammals express six different isoforms of actin in a tissue- and temporal-specific manner (1). Mutations in each isoform have been linked to specific diseases in humans, and in most instances a mutation in one of the two copies of the gene is sufficient to cause the disease (2). Mutations in α-smooth muscle isoactin (αSMA) cause vascular defects leading primarily to thoracic aneurysm and dissection (TAAD). In PNAS, Lu et al. (3) addresses two of these mutations, primarily R258C and secondarily R258H, to try to gain insight into how changes induced by these mutations lead to TAAD by affecting actin function. Vascular material from an affected individual carrying the R258C mutation shows that the muscle layer of the vessel wall is abnormal, with disorganized structure and a dearth of contractile filaments compared with normal smooth muscle, suggesting abnormal filament assembly, protein instability, or failure of the assembled cytoskeleton to withstand the forces imposed on it by myosin during contraction of the muscle (4, 5). However, the advanced disease stage at the time of tissue resection prevents early stages of the disease from being addressed. This same site has been mutated in other actin isoforms, in each case leading to a disease. An R256 mutation to either H or L in α-skeletal muscle isoactin causes nemaline myopathy and an R256W mutation in β-nonmuscle isoactin causes Baraitser–Winter Syndrome (2).