{Reference Type}: Journal Article
{Title}: Somatic RIT1 delins in arteriovenous malformations hyperactivate RAS-MAPK signaling amenable to MEK inhibition.
{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;
{Journal}: Angiogenesis
{Volume}: 0
{Issue}: 0
{Year}: 2024 Jul 5
{Factor}: 10.658
{DOI}: 10.1007/s10456-024-09934-8
{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.