The ACTA2 gene encodes actin α2, a major smooth muscle protein in vascular smooth muscle cells. Missense variants in the ACTA2 gene can cause inherited thoracic aortic diseases with characteristic symptoms, such as dysfunction of smooth muscle cells in the lungs, brain vessels, intestines, pupils, bladder, or heart. We identified a heterozygous missense variant of Gly148Arg (G148R) in a patient with a thoracic aortic aneurysm, dissection, and left ventricular non-compaction. We used zebrafish as an in vivo model to investigate whether or not the variants might cause functional or histopathological abnormalities in the heart. Following the fertilization of one-cell stage embryos, we injected in vitro synthesized ACTA2 mRNA of wild-type, novel variant G148R, or the previously known pathogenic variant Arg179His (R179H). The embryos were maintained and raised for 72 h post-fertilization for a heart analysis. Shortening fractions of heart were significantly reduced in both pathogenic variants. A histopathological evaluation showed that the myocardial wall of ACTA2 pathogenic variants was thinner than that of the wild type, and the total cell number within the myocardium was markedly decreased in all zebrafish with pathogenic variants mRNAs. Proliferating cell numbers were also significantly decreased in the endothelial and myocardial regions of zebrafish with ACTA2 variants compared to the wild type. These results demonstrate the effects of ACTA2 G148R and R179H on the development of left ventricle non-compaction and cardiac morphological abnormalities. Our study highlights the previously unknown significance of the ACTA2 gene in several aspects of cardiovascular development.

ACTA2基因编码肌动蛋白 α2，这是血管平滑肌细胞中的一种主要平滑肌蛋白。 ACTA2基因的错义变异可导致具有特征性症状的遗传性胸主动脉疾病，例如肺、脑血管、肠、瞳孔、膀胱或心脏中平滑肌细胞的功能障碍。我们在一名患有胸主动脉瘤、夹层和左心室致密化不全的患者中发现了 Gly148Arg (G148R) 的杂合错义变异。我们使用斑马鱼作为体内模型来研究这些变异是否可能导致心脏功能或组织病理学异常。单细胞阶段胚胎受精后，我们注射体外合成的野生型新变体 G148R 或先前已知的致病变体 Arg179His (R179H) 的ACTA2 mRNA。受精后将胚胎维持并培养 72 小时以进行心脏分析。两种致病变异的心脏缩短分数均显着降低。组织病理学评估表明， ACTA2致病变异的心肌壁比野生型的心肌壁更薄，并且所有带有致病变异mRNA的斑马鱼心肌内的细胞总数显着减少。与野生型相比， ACTA2变体斑马鱼的内皮和心肌区域的增殖细胞数量也显着减少。这些结果证明了ACTA2 G148R 和 R179H 对左心室致密化不全和心脏形态异常的发展的影响。我们的研究强调了ACTA2基因在心血管发育的几个方面中以前未知的重要性。