Abstract：
Unilateral moyamoya disease (MMD) represents a distinct subtype characterised by occlusive changes in the circle of Willis and abnormal vascular network formation. However, the aetiology and pathogenesis of unilateral MMD remain unclear. In this study, genetic screening of a family with unilateral MMD using whole-genome sequencing helped identify the c.1205 C > A variant of FOXM1, which encodes the transcription factor FOXM1 and plays a crucial role in angiogenesis and cell proliferation, as a susceptibility gene mutation. We demonstrated that this mutation significantly attenuated the proangiogenic effects of FOXM1 in human brain endothelial cells, leading to reduced proliferation, migration, and tube formation. Furthermore, FOXM1 c.1205 C > A results in increased apoptosis of human brain endothelial cells, mediated by the downregulation of the transcription of the apoptosis-inhibiting protein BCL2. These results suggest a potential role for the FOXM1 c.1205 C > A mutation in the pathogenesis of unilateral MMD and may contribute to the understanding and treatment of this condition.
摘要：
单侧烟雾病（MMD）代表一种独特的亚型，其特征是Willis环的闭塞变化和异常的血管网络形成。然而,单侧MMD的病因和发病机制尚不清楚.在这项研究中,使用全基因组测序对单侧MMD家族进行遗传筛选有助于鉴定FOXM1的c.1205C>A变体，该变体编码转录因子FOXM1，并在血管生成和细胞增殖中起关键作用，作为易感基因突变。我们证明了这种突变显著减弱了FOXM1在人脑内皮细胞中的促血管生成作用,导致扩散减少，迁移,和管的形成。此外，FOXM1c.1205C>A导致人脑内皮细胞凋亡增加，由凋亡抑制蛋白BCL2的转录下调介导。这些结果表明FOXM1c.1205C>A突变在单侧MMD的发病机理中具有潜在作用，并且可能有助于对这种情况的理解和治疗。
