Somatic Variants in SVIL in Cerebral Aneurysms.
Somatic Variants in SVIL in Cerebral Aneurysms.
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DOI：
10.1212/nxg.0000000000200040
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发表时间：
2022-12
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虽然体细胞突变在癌症中已得到充分研究，但它们在其他复杂特征中的作用却知之甚少。我们的目标是识别可能导致囊状脑动脉瘤形成的体细胞变异。我们对动脉瘤组织和配对外周血进行了全外显子组测序。然后使用 RNA 测序和 CRISPR/Cas9 系统对我们的结果进行功能验证。在 17% 的动脉瘤组织中发现了参与超级绒毛蛋白 (SVIL) 或其调节的体细胞变异。当SVIL基因发生突变时，与正常对照血管相比，动脉瘤组织中SVIL的表达水平下调。通过评估基因表达和蛋白激酶磷酸化的变化，确定血管平滑肌细胞 (vSMC) 中通过 CRISPR/Cas9 系统敲低 SVIL 所诱导的下游信号通路。我们发现SVIL通过Krüppel样因子4和血小板衍生生长因子调节vSMCs的表型调节至合成表型，并通过RhoA/ROCK途径影响vSMCs的细胞迁移。我们认为体细胞变异形成了脑动脉瘤发展的新机制。具体来说，SVIL 中的体细胞变异会导致 vSMC 的表型调节，从而增加动脉瘤形成的易感性。这一发现为脑动脉瘤的治疗干预和预防提供了新途径。
While somatic mutations have been well-studied in cancer, their roles in other complex traits are much less understood. Our goal is to identify somatic variants that may contribute to the formation of saccular cerebral aneurysms. We performed whole-exome sequencing on aneurysm tissues and paired peripheral blood. RNA sequencing and the CRISPR/Cas9 system were then used to perform functional validation of our results. Somatic variants involved in supervillin (SVIL) or its regulation were found in 17% of aneurysm tissues. In the presence of a mutation in the SVIL gene, the expression level of SVIL was downregulated in the aneurysm tissue compared with normal control vessels. Downstream signaling pathways that were induced by knockdown of SVIL via the CRISPR/Cas9 system in vascular smooth muscle cells (vSMCs) were determined by evaluating changes in gene expression and protein kinase phosphorylation. We found that SVIL regulated the phenotypic modulation of vSMCs to the synthetic phenotype via Krüppel-like factor 4 and platelet-derived growth factor and affected cell migration of vSMCs via the RhoA/ROCK pathway. We propose that somatic variants form a novel mechanism for the development of cerebral aneurysms. Specifically, somatic variants in SVIL result in the phenotypic modulation of vSMCs, which increases the susceptibility to aneurysm formation. This finding suggests a new avenue for the therapeutic intervention and prevention of cerebral aneurysms.