小児クローン病の新たな遺伝的原因を発見 (Medicine: Cause of Chronic Inflammatory Bowel Disease in Children Discovered)

2026-06-25

2026-06-24 ミュンヘン大学（LMU）

Ludwig Maximilian University of Munich（LMU）の研究チームは、国際共同研究により、小児を中心とする重症のCrohn’s diseaseの新たな原因遺伝子としてBIRC3を同定した。研究では、10家系14人の患者を対象に遺伝子解析、トランスクリプトーム解析、プロテオーム解析および実験モデルを用いて病態を解明した。その結果、BIRC3の機能喪失変異により腸上皮細胞でRIPK1シグナル伝達経路が異常に活性化し、細胞死が増加して腸粘膜のバリア機能が損なわれ、慢性的な腸炎が引き起こされることを明らかにした。さらに、このシグナル経路は稀な単一遺伝子性クローン病だけでなく、より一般的なクローン病にも関与する可能性が示された。本研究は、希少疾患の解析が炎症性腸疾患全体の病態理解につながることを示すとともに、BIRC3やRIPK1を標的とした新たな精密医療や分子標的治療の開発に向けた重要な知見を提供した。

＜関連情報＞

BIRC3（細胞性アポトーシス阻害タンパク質2をコードする遺伝子）の変異は、受容体相互作用タンパク質キナーゼ1シグナル伝達の調節異常を引き起こし、上皮細胞死の増加につながり、単一遺伝子性クローン病と関連している BIRC3 (Encoding Cellular Inhibitor of Apoptosis Protein 2) Variants Result in Dysregulated Receptor-Interacting Protein Kinase 1 Signaling Leading to Increased Epithelial Cell Death and Are Associated With Monogenic Crohn’s Disease

Qi Li ∙ Ryusuke Nambu ∙ Hu Yaqiang ∙ … ∙ Daniel Kotlarz ∙ Dali Li ∙ Aleixo M. Muise
Gastroenterology Published:June 23, 2026
DOI:https://doi.org/10.1053/j.gastro.2026.05.022

Abstract

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 (cIAP2^H312Y/+) 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 cIAP2^H312Y/+ mice.