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Li, Q.* ; Nambu, R.* ; Yaqiang, H.* ; Shen, X.* ; Argmann, C.* ; Guan, R.* ; Janssen, E.* ; Le Voyer, T.* ; Warner, N.* ; Yu, D.D.* ; Guo, J.* ; Long, K.* ; Ouahed, J.* ; Field, M.* ; Collen, L.* ; Bibus, J.* ; Illig, D.* ; Rohlfs, M.* ; Yu, Z.* ; Yang, S.* ; Li, W.* ; Platt, C.D.* ; Comella, P.H.* ; Jordan, D.* ; Suárez-Fariñas, M.* ; Alosaimi, M.F.* ; Peters, L.A.* ; Rosain, J.* ; Fieschi, C.* ; Puel, A.* ; Hsieh, E.W.Y.* ; Naito, T.* ; Zeng, Z.* ; Rodríguez-Belvís, M.V.* ; Palomino, L.* ; Küster, P.* ; Li, D.* ; Klein, C.* ; Snapper, S.B.* ; Casanova, J.L.* ; Geha, R.* ; Hoffenberg, E.* ; McGovern, D.P.B.* ; Schadt, E.* ; Kotlarz, D.M. ; Li, D.* ; Muise, A.M.*

BIRC3 (Encoding cIAP2) variants result in dysregulated RIPK1 signaling leading to increased epithelial cell death and are associated with monogenic crohn’s disease.

Gastroenterology, DOI: 10.1053/j.gastro.2026.05.022 (2026)
Postprint DOI PMC
Open Access Green
Background & Aims: Tumor necrosis factor (TNF) is a key driver of intestinal epithelial inflammation. The baculoviral inhibitor of apoptosis protein repeat-containing 3 (BIRC3) gene encodes the cellular inhibitor of apoptosis protein 2 (cIAP2), a known regulator of TNF signaling. Although genetic variants in components of the TNF signaling pathway have been reported, no human BIRC3 variants have been previously identified. Methods: We screened exomes obtained from Crohn’s disease (CD) patients from multiple centers for BIRC3 variants. We used cellular, mouse organoids, induced pluripotent stem cells–derived intestinal organoids, knock-in and knockout mouse models, and knockout zebrafish, as well as transcriptome analysis of various samples to determine pathogenicity of BIRC3 variants. Results: Rare and damaging BIRC3 variants were identified in 14 patients from 10 unrelated families with CD diagnosed between infancy and adulthood. Functional studies showed that BIRC3 deficiency caused impaired receptor-interacting protein kinase 1 (RIPK1) ubiquitylation, leading to RIPK1 autophosphorylation resulting in increased epithelial cell death. The p.H312Y cIAP2 variant identified in both our index and in another independent patient was mislocalizaed, and a knock-in mouse model of this BIRC3 variant (cIAP2H312Y/+) had exacerbation of chemically induced colitis, whereas ciap1−/+ zebrafish developed spontaneous colitis. Transcriptome analysis of mice organoids and zebrafish showed that BIRC3 deficiency led to inappropriate sustained activation of TNF-responsiveness genes in the absence of stimuli. Small molecule pharmacologic inhibition of RIPK1 or caspases attenuated intestinal inflammation in BIRC3-deficient intestinal organoids and cIAP2H312Y/+ mice. Conclusions: We establish BIRC3 deficiency as a cause of monogenic CD in both pediatric- and adult-onset patients and identify RIPK1 as a therapeutic target.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Birc3 ; Ciap2 ; Monogenic Ibd ; Ripk1
ISSN (print) / ISBN 0016-5085
e-ISSN 1528-0012
Journal Gastroenterology
Publisher Elsevier
Reviewing status Peer reviewed
Institute(s) Institute of Translational Genomics (ITG)