%0 Journal Article
%T Somatic RIT1 delins in arteriovenous malformations hyperactivate RAS-MAPK signaling amenable to MEK inhibition.
%A Kapp FG
%A Bazgir F
%A Mahammadzade N
%A Mehrabipour M
%A Vassella E
%A Bernhard SM
%A Döring Y
%A Holm A
%A Karow A
%A Seebauer C
%A Platz Batista da Silva N
%A Wohlgemuth WA
%A Oppenheimer A
%A Kröning P
%A Niemeyer CM
%A Schanze D
%A Zenker M
%A Eng W
%A Ahmadian MR
%A Baumgartner I
%A Rössler J
%J Angiogenesis
%V 0
%N 0
%D 2024 Jul 5
%M 38969873
%F 10.658
%R 10.1007/s10456-024-09934-8
%X 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.