KREMEN2, an inhibitor of NF-kB-mediated auto-inflammation involved in human genetic disease – KREM-AIF

We recently identified a homozygous private mutation targeting the KREMEN2 gene in a multiple consanguineous family with autoinflammatory disease (AID) of unknown aetiology. Two members of the family were strongly affected, in particular a systemic inflammation associated with severe skin manifestations. KREMEN2 encodes a transmembrane protein that is currently described to have only one function as an inhibitor of the Wnt/ß-catenin signaling pathway. This gene plays an important role in embryonic development, bone formation, tumorigenesis. Our preliminary work revealed that the mutation in KREMEN2 led to loss of the NF-?B signaling pathway inhibition. Because NF-?B is a central player in the immune responses through its controls of DNA transcription, cytokine production and cell survival, we postulate that KREMEN2 might be involved into a broader spectrum of AIDs for which NF-?B signaling pathway is dysregulated.

Our major aim is now to deep-characterize KREMEN2 activity in regard to this new function. For this purpose, we propose to study KREMEN2 in AID around three axes : molecular, cellular and therapeutic using in-vitro, ex-vivo and in-vivo approaches.
Our proposal is :
i) To analyse the KREMEN2 expression in healthy and pathological conditions using NGS and Third-Generation Sequencing (TGS).
ii) To characterize signaling pathways controlled by KREMEN2 (KREMEN2's partners, target genes, cell specificities).
iii) To study in vivo KREMEN2 functions and screen for drugs targeting KREMEN2 signaling pathways.
The output of this project will be:
· To understand how splicing of KREMEN2 modulates its functions.
· To discover new candidate genes involved in AID and identify dysfunction of KREMEN2 signalling in AID-related diseases.
. To identify new NF-KB inhibitors, therapeutic tracks to treat inflammatory and AID.