新发现的人类SCCM基因RNF213失功能状态下致脑异常静脉形成的MAPK信号通路机制

人类散发性脑海绵状血管畸形（SCCM）的责任基因不明。我们近期的研究，对31例SCCM患者进行外显子组测序，新发现5例（16.1%）存在RNF213有害杂合突变，推理是SCCM的责任基因。在自创的两个品系的rnf213-/-（rnf213失功能状态下）斑马鱼中，发现了与人类SCCM高度相似的脑异常静脉血管表型（静脉血管发生、桑葚样表型、畸形血管无或慢血流），RNA-seq和RT-qPCR证实该模型的kbtbd7、anxa6基因表达下调，表型拯救证实脑异常静脉血管网部分逆转，但其形成机制不明。拟建立SCCM临床队列，行外显子组测序、7T MRI/SWI检查及病变组织生物学特征分析，发现其静脉异常/静脉构筑的特点及其与RNF213有害突变的关联；并在自创新的rnf213-/-斑马鱼、Rnf213-/-小鼠模型中进一步比较验证以脑静脉异常为核心标志的MAPK信号通路机制，为诊断和治疗提供新靶标。

The gene responsible for sporadic cerebral cavernous malformation (SCCM) is unidentified. In our recent study, among 31 SCCM patients, we identified 5(16.1%) patients carrying 6 heterozygous deleterious mutations of RNF213(Ring finger protein 213 gene) by whole exome sequencing. Thus we identified RNF213 as a novel candidate gene for human SCCM. In our previous study, we successfully generated two rnf213-/-mutant lines using zebrafish model and found some abnormal cerebral venous phenotypes (venogenesis, mulberry-like phenotype, disordered or slow flow in malformations), which was reminiscent of human cerebral cavernous malformation. RNA-seq and subsequent RT-qPCR demonstrated that the expression level of kbtbd7 and anxa6 in the rnf213 mutants were significantly downregulated. What’s more, the abnormal cerebral vein was rescued partly after kbtbd7 mRNA or anxa6 mRNA injection, but the underlying mechanism of abnormal cerebral vein formation is unclear. To explore the potential molecular mechanism, a clinical SCCM cohort should be established, and subsequent whole exome sequencing, 7T MRI/SWI imaging and biological characteristics of the lesion would be analyzed in patients, to reveal the correlation between venous abnormalities and RNF213 gene mutations. Finally, we would further verify the MAPK signal pathway, which may involve in the formation of cerebral venous abnormalities, in the self-established rnf213-/- zebrafish and Rnf213-/- mouse.This study will supply the new diagnostic and/or therapeutic targets (abnormal cerebral venous) for SCCM patients.