Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China.
Department of Neurology, Jiangmen Central Hospital, Jiangmen, China.
J Cereb Blood Flow Metab. 2021 Jun;41(6):1251-1263. doi: 10.1177/0271678X20914996. Epub 2020 Apr 4.
Although familial forms of cerebral cavernous malformation are mainly attributed to three genes (, and ), no mutation is identified in sporadic cerebral cavernous malformation cases with a unique lesion, indicating additional genes for sporadic cerebral cavernous malformation. To screen the candidate genes, we conducted whole exome sequencing in 31 sporadic cerebral cavernous malformation patients and 32 healthy controls, and identified 5 affected individuals carrying 6 heterozygous deleterious mutations in but no mutation in healthy individuals. To further confirm was associated with cerebral cavernous malformation, we generated homozygous knockout zebrafish and found mutation of in zebrafish led to a mulberry-like cluster of disordered-flow vascular channels which was reminiscent of human cerebral cavernous malformation. In addition, we revealed and were significantly downregulated due to mutation through transcriptomic sequencing and RT-qPCR analysis. Based on the mulberry-like phenotype partly rescued by mRNA of as well as , we suggested that promoted mulberry-like cluster via downregulation of and . Altogether, we firstly demonstrate is a novel candidate gene for sporadic cerebral cavernous malformation and the mutation of is responsible for the mulberry-like cluster in zebrafish.
尽管家族性脑动静脉畸形主要归因于三个基因（KRIT1、CCM2 和 MAGI2），但在具有独特病变的散发性脑动静脉畸形病例中并未发现突变，这表明散发性脑动静脉畸形存在其他候选基因。为了筛选候选基因，我们对 31 名散发性脑动静脉畸形患者和 32 名健康对照进行了全外显子组测序，发现 5 名受影响的个体携带 6 个杂合性有害突变，但在健康个体中未发现 突变。为了进一步证实 与脑动静脉畸形有关，我们生成了 纯合性敲除斑马鱼，并发现 突变导致类似桑葚的紊乱血流血管簇，类似于人类脑动静脉畸形。此外，我们通过转录组测序和 RT-qPCR 分析发现，由于 突变， 和 显著下调。基于 通过 mRNA 部分挽救的桑葚样表型，我们认为 通过下调 和 促进桑葚样簇的形成。总之，我们首次证明 是散发性脑动静脉畸形的一个新的候选基因， 突变导致斑马鱼中出现桑葚样簇。
