Reference - Detail
| RRC ID | 85673 |
|---|---|
| Author | 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. |
| Title | Somatic RIT1 delins in arteriovenous malformations hyperactivate RAS-MAPK signaling amenable to MEK inhibition. |
| Journal | Angiogenesis |
| 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. |
| Volume | 27(4) |
| Pages | 739-752 |
| Published | 2024-11-1 |
| DOI | 10.1007/s10456-024-09934-8 |
| PII | 10.1007/s10456-024-09934-8 |
| PMID | 38969873 |
| PMC | PMC11564399 |
| MeSH | Animals Arteriovenous Malformations* / drug therapy Arteriovenous Malformations* / genetics Arteriovenous Malformations* / metabolism Arteriovenous Malformations* / pathology Female HEK293 Cells Humans MAP Kinase Signaling System* / drug effects Male Protein Kinase Inhibitors / pharmacology Pyridones / pharmacology Pyrimidinones / pharmacology Zebrafish* / embryology ras Proteins* / genetics ras Proteins* / metabolism |
| IF | 9.78 |
| Altmetric score |
オルトメトリクス指標項目
|
| The most frequently cited source | Clinical guideline |
| Total number of mentions | 1 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Zebrafish | UAS:RFP |