Somatic RIT1 delins in arteriovenous malformations hyperactivate RAS-MAPK signaling amenable to MEK inhibition
Kapp FG, Bazgir F, Mahammadzade N, Mehrabipour M, Vassella E, Bernhard SM, Döring Y, Holm A, Karow A, Seebauer C, Platz Batista da Silva N, Wohlgemuth WA, Oppenheimer A, Kröning P, Niemeyer CM, Schanze D, Zenker M, Eng W, Ahmadian MR, Baumgartner I, Rössler J (2024)
Publication Language: English
Publication Type: Journal article
Publication year: 2024
Journal
DOI: 10.1007/s10456-024-09934-8
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.
Authors with CRIS profile
Involved external institutions
Universitätsklinikum Freiburg
Germany (DE)
Universitätsklinikum Düsseldorf
Germany (DE)
Universität Bern
Switzerland (CH)
Universitätsklinikum Regensburg
Germany (DE)
Inselspital, Universitätsspital Bern
Switzerland (CH)
Martin-Luther-Universität Halle-Wittenberg (MLU)
Germany (DE)
Universitätsklinikum Magdeburg A.ö.R.
Germany (DE)
Boston Children's Hospital
United States (USA) (US)
Germany (DE)
Universitätsklinikum Düsseldorf
Germany (DE)
Universität Bern
Switzerland (CH)
Universitätsklinikum Regensburg
Germany (DE)
Inselspital, Universitätsspital Bern
Switzerland (CH)
Martin-Luther-Universität Halle-Wittenberg (MLU)
Germany (DE)
Universitätsklinikum Magdeburg A.ö.R.
Germany (DE)
Boston Children's Hospital
United States (USA) (US)
How to cite
APA:
Kapp, F.G., Bazgir, F., Mahammadzade, N., Mehrabipour, M., Vassella, E., Bernhard, S.M.,... Rössler, J. (2024). Somatic RIT1 delins in arteriovenous malformations hyperactivate RAS-MAPK signaling amenable to MEK inhibition. Angiogenesis. https://doi.org/10.1007/s10456-024-09934-8
MLA:
Kapp, Friedrich G., et al. "Somatic RIT1 delins in arteriovenous malformations hyperactivate RAS-MAPK signaling amenable to MEK inhibition." Angiogenesis (2024).
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