Kapp, Friedrich G; Bazgir, Farhad; Mahammadzade, Nagi; Mehrabipour, Mehrnaz; Vassella, Erik; Bernhard, Sarah M; Döring, Yvonne; Holm, Annegret; Karow, Axel; Seebauer, Caroline; Platz Batista da Silva, Natascha; Wohlgemuth, Walter A; Oppenheimer, Aviv; Kröning, Pia; Niemeyer, Charlotte M; Schanze, Denny; Zenker, Martin; Eng, Whitney; Ahmadian, Mohammad R; Baumgartner, Iris; ... (2024). Somatic RIT1 delins in arteriovenous malformations hyperactivate RAS-MAPK signaling amenable to MEK inhibition. (In Press). Angiogenesis Springer 10.1007/s10456-024-09934-8
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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.
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