脑脊髓血管畸形作为一种先天性脑血管疾病，其遗传致病机制一直未明确。近期包括本研究组在内的多个团队在重要杂志相继报道了KRAS/BRAF/MAPK通路体细胞突变在脑脊髓动静脉畸形发生中具有核心作用，是目前该疾病致病机制的重要突破，但仍有部分血管畸形病例无法以该通路突变解释。我们在前期研究中，在KRAS/BRAF突变阴性患者中发现了RASAL2体细胞突变，该突变在肿瘤中通过加速Ras介导的GTP水解调控了Ras/MAPK通路激活，我们推测其在内皮细胞中有类似作用，从而参与脑脊髓血管畸形的发病。本研究将：1)在更大的疾病队列中寻找RASAL2基因体细胞突变，2)在细胞模型中通过过表达和敲减RASAL2，探索该基因对内皮细胞的作用，3)在病变组织内皮细胞和斑马鱼模型上研究患病RASAL2突变的致病机制。本研究将完善血管畸形的KRAS/BRAF/MAPK通路致病假说，为该疾病靶向性药物治疗提供思路。

Cerebrospinal arteriovenous malformation is a group of congenital disease, and its pathogenesis remains unclear. Recently, with the effort of our research group along with several others, a central role for somatic mutations involving the tumor-related KRAS/BRAF/MAPK pathway in the development of AVM has been established . However, there are still cases without detection of mutations in the core pathway. We applied whole exome sequencing to these cases and found RASAL2 somatic mutations in 2 KRAS/BRAF-negative patients. RASAL2 encodes a RasGAP which suppresses Ras/MAPK pathway activation by accelerating Ras-mediated GTP hydrolysis. Loss-of-function mutation in RASAL2 has been reported in various tumor types, hence we speculate that a similar mechanism may work in endothelial cells, where somatic mutations in RASAL2 participate in the onset of cerebrospinal vascular malformations. This study will : 1) look for somatic mutations in the RASAL2 in a larger validation cohort, 2) explore the role of RASAL2 in vascular development by gene overexpression and knock-down in an endothelial cell model, and 3) study the pathogenicity of RASAL2 mutations in endothelial cells isolated from mutation-carrying nidus and zebrafish models. This study will further validate the KRAS/BRAF/MAPK central pathway hypothesis of arteriovenous malformation and will provide insight for development of targeted drug therapy.