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PNAS Plus Significance Statements

Point mutations in vascular smooth muscle α-actin are the most prevalent cause of familial thoracic aortic aneurysms leading to acute dissections, yet the molecular mechanism by which these mutations affect actin function is unknown. An underlying cause of the disease is thought to be contractile dysfunction, which initiates adaptive pathways to repair the defects in the smooth muscle cells. Here, we investigate the effects of the R258C mutation, a prevalent mutation in humans with a poor prognosis. The mutant actin shows multiple defects, including impaired interaction with myosin, formation of less stable filaments, and enhanced levels of monomer. These defects are likely to decrease cellular force production and initiate aberrant mechanosensing pathways that culminate in the disease. (See pp. E4168–E4177.)