Somatic RIT1 delins in arteriovenous malformations hyperactivate RAS-MAPK signaling amenable to MEK inhibition

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

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• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: Angiogenesis. - 27, 4 (2024) , 739-752, ISSN: 1573-7209

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2024
• Creator: Kapp, Friedrich ; Bazgir, Farhad ; Mahammadzade, Nagi ; Mehrabipour, Mehrnaz ; Vassella, Erik ; Bernhard, Sarah M. ; Döring, Yvonne ; Holm, Annegret Elisabeth ; Karow, Axel ; Seebauer, Caroline T. ; Platz Batista da Silva, Natascha ; Wohlgemuth, Walter A. ; Oppenheimer, Aviv ; Kröning, Pia ; Niemeyer, Charlotte ; Schanze, Denny ; Zenker, Martin ; Eng, Whitney ; Baumgartner, Iris ; Ahmadian, Mohammad Reza ; Rößler, Jochen

Further information

• DOI: 10.1007/s10456-024-09934-8
• URN: urn:nbn:de:bsz:25-freidok-2553729
• Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.