Journal Article
Somatic RIT1 delins in arteriovenous malformations hyperactivate RAS-MAPK signaling amenable to MEK inhibition
Friedrich G. Kapp; Farhad Bazgir; Nagi Mahammadzade; Mehrnaz Mehrabipour; Erik Vassella; Sarah M. Bernhard; Yvonne Döring; Annegret Holm; Axel Karow; Caroline Seebauer; Natascha Platz Batista da Silva; Walter A. Wohlgemuth; Aviv Oppenheimer; Pia Kröning; Charlotte M. Niemeyer; Denny Schanze; Martin Zenker; Whitney Eng; Mohammad R. Ahmadian; Iris Baumgartner; Jochen Rössler
Angiogenesis · Vol. 27, Issue 4 · pp. 739-752 · 2024
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.