Investigating IPO8-dependent immune dysregulation of the GUT: from mechanism to precision medicine – IPOGUT

A novel connective tissue disorder combining vascular and skeletal abnormalities has been recently associated to bi-allelic loss of function variants in IPO8. IPO8 codes for importin 8, a member of the ?-karyopherin family involved in cytoplasm-to-nucleus shuttling of a broad range of cargos. We have shown in zebrafish, that importin 8 plays a critical role during early stage of development by controlling Smad nuclear translocation and downstream TGF-?/BMP-dependent transcription (Ziegler A, 2021). In our cohort, strikingly, 50 % of IPO8 deficient patients present immune-dysregulation features and notably intestinal inflammation. Predisposition to inflammatory diseases has been already observed in Loeys-Dietz syndrome and is thus compatible with defective TGF-? signaling (Frischmeyer-Guerrerio P, 2013). Preliminary data indicate that mice deficient in IPO8 variably develop rectal prolapse, a symptom of intestinal inflammation. By undertaking a multilayered approach in both IPO8 deficient patients and in animal models of the disease, our proposal aims at 1-completing and extending our work elucidating the molecular and cellular consequences of IPO8 deficiency in humans; 2-exploring the role of ipo8 in TGF-? dependent and independent signaling and intestinal immune homeostasis in a mouse model; 3- harnessing our established ipo8-/- zebrafish model as screening platform to identify individualized therapeutic strategies. The output of our project will bridge the gap between the elucidation of the molecular mechanism underlying IPO8 deficiency and the development of individualized therapeutic strategies with the ultimate goal to step forward diagnostic and management of this group of rare and severe patients.