Work

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

Year: 2023

Type: preprint

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 somatic RIT1 indel 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 expressed RIT1 variants in HEK293T cells, which led to a strong increase in ERK1/2 phosphorylation. Endothelial-specific mosaic overexpression of the RIT1 indels in zebrafish embryos induced AVM formation, highlighting the functional importance in vascular development. Both ERK1/2 hyperactivation in vitro and AVM formation in vivo could 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 identifying RIT1 as a novel gene involved in AVM formation and pave the way for targeted treatment and clinical trials in patients with AVM.

Source: medRxiv

DOI: 10.1101/2023.11.13.23298448