Kapp, Friedrich G. and Bazgir, Farhad and Mahammadzade, Nagi and Mehrabipour, Mehrnaz and Vassella, Erik and Bernhard, Sarah M. and Doering, Yvonne and Holm, Annegret and Karow, Axel and Seebauer, Caroline and da Silva, Natascha Platz Batista and Wohlgemuth, Walter A. and Oppenheimer, Aviv and Kroening, Pia and Niemeyer, Charlotte M. and Schanze, Denny and Zenker, Martin and Eng, Whitney and Ahmadian, Mohammad R. and Baumgartner, Iris and Roessler, Jochen (2024) Somatic RIT1 delins in arteriovenous malformations hyperactivate RAS-MAPK signaling amenable to MEK inhibition. ANGIOGENESIS, 27 (4). pp. 739-752. ISSN 0969-6970, 1573-7209
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | MUTATIONS; Vascular anomalies; Vascular malformation; Arteriovenous malformation; RIT1; RAS-MAPK pathway; Trametinib |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Hals-Nasen-Ohren-Heilkunde Medicine > Lehrstuhl für Röntgendiagnostik |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 17 Dec 2025 09:47 |
| Last Modified: | 17 Dec 2025 09:47 |
| URI: | https://pred.uni-regensburg.de/id/eprint/65332 |
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