Identification of rare, damaging BIRC3 variants in patients with monogenic Crohn’s disease (CD) across ages.
BIRC3 deficiency disrupts receptor-interacting protein kinase 1 (RIPK1) ubiquitylation, leading to increased intestinal epithelial cell death through autophosphorylation of RIPK1.
Functional and transcriptomic analyses in cellular, mouse, and zebrafish models demonstrate dysregulated TNF signaling and spontaneous intestinal inflammation due to BIRC3 variants.
Pharmacological inhibition of RIPK1 or caspases mitigates intestinal inflammation, highlighting RIPK1 as a viable therapeutic target in BIRC3-deficient CD.
