Somatic RIT1 indels identified in arteriovenous malformations hyperactivate RAS-MAPK signaling and are amenable to MEK inhibition

Abstract

Arteriovenous malformations (AVM) are benign vascular anomalies prone to pain, bleeding, and progressive growth. Treatment is often difficult and relapse after therapy is common. AVM are mainly caused by somatic mosaicism with pathogenic variants of the RAS-MAPK pathway. However, a causative variant is not identified in all patients. Using ultra-deep next generation sequencing we identified novel somaticRIT1indel variants in lesional tissue of three AVM patients.RIT1– not previously implicated in AVM development – encodes a RAS-like protein that can modulate RAS-MAPK signaling. For biochemical characterization, we expressedRIT1variants in HEK293T cells, which led to a strong increase in ERK1/2 phosphorylation. Endothelial-specific mosaic overexpression of theRIT1indels in zebrafish embryos induced AVM formation, highlighting the functional importance in vascular development. Both ERK1/2 hyperactivationin vitroand AVM formationin vivocould be suppressed by pharmacological MEK inhibition. Targeted treatment with the MEK inhibitor trametinib led to a significant decrease in bleeding episodes and AVM size in one patient. Our findings expand the genetic spectrum of AVM by identifyingRIT1as a novel gene involved in AVM formation and pave the way for targeted treatment and clinical trials in patients with AVM.