PUBLICATION
Somatic RIT1 delins in arteriovenous malformations hyperactivate RAS-MAPK signaling amenable to MEK inhibition
- Authors
- Kapp, F.G., Bazgir, F., Mahammadzade, N., Mehrabipour, M., Vassella, E., Bernhard, S.M., Döring, Y., Holm, A., Karow, A., Seebauer, C., Platz Batista da Silva, N., Wohlgemuth, W.A., Oppenheimer, A., Kröning, P., Niemeyer, C.M., Schanze, D., Zenker, M., Eng, W., Ahmadian, M.R., Baumgartner, I., Rössler, J.
- ID
- ZDB-PUB-240707-10
- Date
- 2024
- Source
- Angiogenesis 27(4): 739-752 (Journal)
- Registered Authors
- Kapp, Friedrich, Mahammadzade, Nagi, Oppenheimer, Aviv
- Keywords
- Arteriovenous malformation, RAS-MAPK pathway, RIT1, Trametinib, Vascular anomalies, Vascular malformation
- MeSH Terms
-
- ras Proteins*/genetics
- ras Proteins*/metabolism
- Protein Kinase Inhibitors/pharmacology
- Animals
- Female
- Male
- MAP Kinase Signaling System*/drug effects
- Pyrimidinones/pharmacology
- Zebrafish*/embryology
- HEK293 Cells
- Humans
- Arteriovenous Malformations*/drug therapy
- Arteriovenous Malformations*/genetics
- Arteriovenous Malformations*/metabolism
- Arteriovenous Malformations*/pathology
- Pyridones/pharmacology
- PubMed
- 38969873 Full text @ Angiogenesis
Citation
Kapp, F.G., Bazgir, F., Mahammadzade, N., Mehrabipour, M., Vassella, E., Bernhard, S.M., Döring, Y., Holm, A., Karow, A., Seebauer, C., Platz Batista da Silva, N., Wohlgemuth, W.A., Oppenheimer, A., Kröning, P., Niemeyer, C.M., Schanze, D., Zenker, M., Eng, W., Ahmadian, M.R., Baumgartner, I., Rössler, J. (2024) Somatic RIT1 delins in arteriovenous malformations hyperactivate RAS-MAPK signaling amenable to MEK inhibition. Angiogenesis. 27(4):739-752.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping