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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America. >Vascular disease-causing mutation, smooth muscle alpha-actin R258C, dominantly suppresses functions of alpha-actin in human patient fibroblasts
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Vascular disease-causing mutation, smooth muscle alpha-actin R258C, dominantly suppresses functions of alpha-actin in human patient fibroblasts

机译：Vascular disease-causing mutation, smooth muscle alpha-actin R258C, dominantly suppresses functions of alpha-actin in human patient fibroblasts

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摘要

The most common genetic alterations for familial thoracic aortic aneurysms and dissections (TAAD) are missense mutations in vascular smooth muscle (SM) alpha-actin encoded by ACTA2. We focus here on ACTA2-R258C, a recurrent mutation associated with early onset of TAAD and occlusive moyamoya-like cerebrovascular disease. Recent biochemical results with SM alpha-actin-R258C predicted that this variant will compromise multiple actin-dependent functions in intact cells and tissues, but a model system to measure R258C-induced effects was lacking. We describe the development of an approach to interrogate functional consequences of actin mutations in affected patient-derived cells. Primary dermal fibroblasts from R258C patients exhibited increased proliferative capacity compared with controls, consistent with inhibition of growth suppression attributed to SM alpha-actin. Telomerase-immortalized lines of control and R258C human dermal fibroblasts were established and SM alpha-actin expression induced with adenovirus encoding myocardin-related transcription factor A, a potent coactivator of ACTA2. Two-dimensional Western blotting confirmed induction of both wild-type and mutant SM alpha-actin in heterozygous ACTA2-R258C cells. Expression of mutant SM alpha-actin in heterozygous ACTA2-R258C fibroblasts abrogated the significant effects of SM alpha-actin induction on formation of stress fibers and focal adhesions, filamentous to soluble actin ratio, matrix contraction, and cell migration. These results demonstrate that R258C dominantly disrupts cytoskeletal functions attributed to SM alpha-actin in fibroblasts and are consistent with deficiencies in multiple cytoskeletal functions. Thus, cellular defects due to this ACTA2 mutation in both aortic smooth muscle cells and adventitial fibroblasts may contribute to development of TAAD and proliferative occlusive vascular disease.

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