Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, VASCERN VASCA European Reference Centre, 79106, Freiburg, Germany.
Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital, Heinrich-Heine University, Düsseldorf, Germany.
Angiogenesis. 2024 Nov;27(4):739-752. doi: 10.1007/s10456-024-09934-8. Epub 2024 Jul 5.
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.
动静脉畸形（AVM）是一种易引起疼痛、出血和进行性生长的良性血管异常。AVM 主要由 RAS-MAPK 通路的镶嵌致病性变异引起。然而，并非所有患者都能确定致病变异。通过超深度测序，我们在 3 名 AVM 患者的病变组织中发现了新型体细胞 RIT1 delins 变异。RIT1 编码一种可以调节 RAS-MAPK 信号的 RAS 样蛋白。我们在 HEK293T 细胞中表达 RIT1 变异体，导致 ERK1/2 磷酸化显著增加。斑马鱼胚胎内皮特异性镶嵌过表达 RIT1 delins 可诱导 AVM 形成，突出了其在血管发育中的功能重要性。体外 ERK1/2 过度激活和体内 AVM 形成均可被 MEK 抑制的药理学抑制所抑制。MEK 抑制剂 trametinib 的治疗导致一名患者出血发作和 AVM 大小显著减少。我们的研究结果表明 RIT1 参与了 AVM 的形成，并为靶向治疗的临床试验提供了依据。
