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

Kapp, Friedrich G.; Bazgir, Farhad; Mahammadzade, Nagi; Vassella, Erik; Döring, Yvonne; Karow, Axel; Seebauer, Caroline; Platz Batista da Silva, Natascha; Wohlgemuth, Walter A.; Krönig, Pia; Niemeyer, Charlotte M.; Schanze, Denny; Zenker, Martin; Eng, Whitney; Ahmadian, Mohammad R.; Baumgartner, Iris; Rössler, Jochen (2023). Somatic RIT1 indels identified in arteriovenous malformations hyperactivate RAS-MAPK signaling and are amenable to MEK inhibition (medRxiv). Cold Spring Harbor Laboratory 10.1101/2023.11.13.23298448

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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.Competing Interest StatementFriedrich G. Kapp has received consulting fees from Novartis. Jochen Rossler is currently an employee of Novartis Pharma. All other authors declare no conflicts of interest.Funding StatementThis study was funded by German Research Foundation (DFG), Foundation for Ageing Research of the HHU Dusseldorf, Walter Benjamin Fellowship from the German Research Foundation and Swiss national Research Foundation, Synergia grant.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:1. Institutional review board of the University Hospital Regensburg, Germany gave ethical approval for this work (17-854-101). 2. Institutional review board of the University Hospital of Bern, Switzerland gave ethical approval for this work (2017-01960). 3. Institutional review board of the Boston Childrens Hospital, Boston, MA, USA gave ethical approval for this work (IRB-P00025772).I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesThe data that support the findings of this study are available from the corresponding author upon reasonable request.

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