Somatic RIT1 delins in arteriovenous malformations hyperactivate RAS-MAPK signaling amenable to MEK inhibition
Year: 2024
Type: article
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.
Source: Angiogenesis
Authors: 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
Institutions: University of Freiburg, University Medical Center Freiburg, Düsseldorf University Hospital, Heinrich Heine University Düsseldorf, University of Bern, University Hospital of Bern, Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, Ludwig-Maximilians-Universität München, Boston Children's Hospital, Harvard University, Friedrich-Alexander-Universität Erlangen-Nürnberg, University Hospital Regensburg, Martin Luther University Halle-Wittenberg, University Hospital Magdeburg, Inserm
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,090
Awards: G1964388840, G2350150859, Mechanismen der vaskulären Wachstumskontrolle bei infantilen Hämangiomen, G5155511607, G5272117078, NARRATIVE - Vaskuläre Anomalien: Dokumentation des natürlichen Krankheitsverlaufs und Erfassung von Lebensqualität und Therapieerfolg durch Patient:inneneingabe, G758616082
OpenAlex ID: W4400354308