Related Experiment Video

Updated: Jun 21, 2025

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

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Somatic RIT1 delins in arteriovenous malformations hyperactivate RAS-MAPK signaling amenable to MEK inhibition

Friedrich G Kapp1, Farhad Bazgir2, Nagi Mahammadzade3

  • 1Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, VASCERN VASCA European Reference Centre, 79106, Freiburg, Germany. friedrich.kapp@uniklinik-freiburg.de.

Angiogenesis
|July 5, 2024
PubMed

Insights

Researchers identified novel RIT1 gene variants in arteriovenous malformations (AVM). Targeting the RAS-MAPK pathway with MEK inhibitors like trametinib shows promise in reducing AVM bleeding and size.

Area of Science:

  • Vascular Biology
  • Genetics
  • Molecular Medicine

Background:

  • Arteriovenous malformations (AVM) are vascular anomalies causing pain and bleeding.
  • Mosaic variants in the RAS-MAPK pathway are implicated in AVM pathogenesis.
  • Causative variants remain unidentified in a subset of AVM patients.

Purpose of the Study:

  • To investigate novel genetic causes of AVM.
  • To explore the role of RIT1 variants in AVM formation and signaling.
  • To assess the therapeutic potential of MEK inhibition in AVM.

Main Methods:

  • Ultra-deep sequencing of lesional AVM tissue.
  • Functional characterization of RIT1 variants in HEK293T cells.
  • In vivo modeling of AVM using zebrafish embryos.
  • Pharmacological inhibition of MEK signaling.

Main Results:

  • Novel somatic RIT1 delins variants were identified in three AVM patients.
  • RIT1 variants caused hyperactivation of ERK1/2 signaling in vitro.
  • Overexpression of RIT1 variants in zebrafish induced AVM formation.
  • MEK inhibition suppressed ERK1/2 hyperactivation and AVM development.
  • Trametinib treatment reduced bleeding and AVM size in a patient.

Conclusions:

  • Somatic RIT1 variants are implicated in the pathogenesis of AVM.
  • RIT1 modulates RAS-MAPK signaling, contributing to vascular development.
  • Targeting MEK with inhibitors like trametinib is a potential therapeutic strategy for AVM.
Keywords:
Arteriovenous malformationRAS-MAPK pathwayRIT1TrametinibVascular anomaliesVascular malformation

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