Abstract：
Arteriovenous malformations (AVM) are benign vascular anomalies prone to pain, bleeding, and progressive growth. AVM are mainly caused by mosaic pathogenic variants of the RAS-MAPK pathway. However, a causative variant is not identified in all patients. Using ultra-deep sequencing, we identified novel somatic RIT1 delins variants in lesional tissue of three AVM patients. RIT1 encodes a RAS-like protein that can modulate RAS-MAPK signaling. We expressed RIT1 variants in HEK293T cells, which led to a strong increase in ERK1/2 phosphorylation. Endothelial-specific mosaic overexpression of RIT1 delins in zebrafish embryos induced AVM formation, highlighting their functional importance in vascular development. Both ERK1/2 hyperactivation in vitro and AVM formation in vivo could be suppressed by pharmacological MEK inhibition. Treatment with the MEK inhibitor trametinib led to a significant decrease in bleeding episodes and AVM size in one patient. Our findings implicate RIT1 in AVM formation and provide a rationale for clinical trials with targeted treatments.
摘要：
动静脉畸形（AVM）是易发生疼痛的良性血管异常，出血,逐步增长。AVM主要由RAS-MAPK途径的马赛克致病变体引起。然而,并非所有患者都能发现致病变异.使用超深度测序，我们在3例AVM患者的病灶组织中发现了新的体细胞RIT1缺失变异。RIT1编码可以调节RAS-MAPK信号传导的RAS样蛋白。我们在HEK293T细胞中表达RIT1变体，这导致ERK1/2磷酸化的强烈增加。斑马鱼胚胎中RIT1蛋白的内皮特异性镶嵌过表达诱导的AVM形成，强调它们在血管发育中的功能重要性。体外ERK1/2的过度活化和体内AVM的形成都可以通过药理学MEK抑制来抑制。用MEK抑制剂曲美替尼治疗导致一名患者的出血事件和AVM大小显著减少。我们的发现暗示RIT1在AVM形成中，并为靶向治疗的临床试验提供了理论基础。
