BIRC3 (encoding cIAP2) variants are associated with Crohn’s Disease.

The baculoviral IAP repeat-containing 3 (BIRC3) gene encodes the Cellular Inhibitor of Apoptosis Protein 2 (cIAP2) a regulator of innate immune pathways including TNFα receptor signaling. We identified 5 heterozygous and 3 homozygous rare damaging BIRC3 variants in 13 patients from 9 independent families who presented with Crohn’s Disease (CD) between 2 months and 31 years of age. A knock-in mouse model of the BIRC3 variant (cIAP2H312Y/+) identified in two independent CD families had increased susceptibility to DSS-induced colitis and ciap−/+ zebrafish developed spontaneous colitis. Transcriptome analysis showed that reduced BIRC3 expression led to the induction of several TNFa responsive genes including NFKB2. Functional studies showed that all cIAP2 variants had impaired inhibition of NFκB2 activity and increased cell death when induced by TNFa. Finally, cIAP2H312Y/+ mice treated with apoptosis or RIPK1 inhibitors had improved clinical outcomes. Our study demonstrates that BIRC3 variants results in dysregulation of NFκB2 signaling leading to in CD.