Evidence map›Paper›PMID 42335979›Full record

ArticleGastroenterology2026

BIRC3 (Encoding cIAP2) Variants Result in Dysregulated RIPK1 Signaling Leading to Increased Epithelial Cell Death and Are Associated With Monogenic Crohn's Disease.

Qi Li, Ryusuke Nambu, Hu Yaqiang, Xiang Shen, Carmen Argmann, Rei Guan, Erin Janssen, Tom Le Voyer, Neil Warner, Daniel D Yu and 37 more

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Article in Gastroenterology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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5 · Who and what money

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47 authors.

Qi LiCell and Systems Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
Ryusuke NambuCell and Systems Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, Saitama Children's Medical Center, Saitama, Japan.
Hu YaqiangShanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China.
Xiang ShenDr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, Ludwig Maximilian University Munich, Munich, Germany.
Carmen ArgmannDepartment of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
Rei GuanCell and Systems Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
Erin JanssenDivision of Pediatric Rheumatology, Michigan Medicine, Ann Arbor, Michigan.
Tom Le VoyerImmunopathology Department, Saint-Louis Hospital, AP-HP, Paris, France; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, and Imagine Institute, Paris Cité University, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York.
Neil WarnerCell and Systems Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
Daniel D YuCell and Systems Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
Jing GuoCell and Systems Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
Kelvin LongCell and Systems Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
Jodie OuahedDivision of Gastroenterology, Hepatology, & Nutrition, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
Michael FieldDivision of Gastroenterology, Hepatology, & Nutrition, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
Lauren CollenDivision of Gastroenterology, Hepatology, & Nutrition, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
Jonas BibusDr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, Ludwig Maximilian University Munich, Munich, Germany.
David IlligDr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, Ludwig Maximilian University Munich, Munich, Germany.
Meino RohlfsDr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, Ludwig Maximilian University Munich, Munich, Germany.
Ziqi YuDr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, Ludwig Maximilian University Munich, Munich, Germany.
Shaohong YangF. Widjaja Foundation Inflammatory Bowel Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
Wenjuan LiCell and Systems Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
Craig D PlattDivision of Immunology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
Phillip H ComellaDepartment of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
Daniel JordanDepartment of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
Mayte Suárez-FariñasDepartment of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
Mohammed F AlosaimiImmunology Research Laboratory, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
Lauren A PetersDepartment of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
Jeremie RosainLaboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, and Imagine Institute, Paris Cité University, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York; Study Center for Immunodeficiencies, Necker Hospital for Sick Children, Paris, France.
Claire FieschiImmunopathology Department, Saint-Louis Hospital, AP-HP, Paris, France.
Anne PuelLaboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, and Imagine Institute, Paris Cité University, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York.
Elena W Y HsiehDivision of Allergy and Immunology, Departments of Pediatrics and Internal Medicine, Children's Medical Center Dallas, University of Texas Southwestern, Dallas, Texas; Department of Immunology, University of Texas Southwestern, Dallas, Texas.
Takeo NaitoDivision of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Zhiyang ZengFengxian Central Hospital Affiliated to Southern Medical University, Shanghai, China.
Marta Velasco Rodríguez-BelvísSección de Gastroenterología y Nutrición Pediátrica, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
Laura PalominoSección de Gastroenterología y Nutrición Pediátrica, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
Peter KüsterDepartment of Paediatrics, Clemens Hospital GmbH Münster, Munster, Nordrhein-Westfalen, Germany.
Dalin LiF. Widjaja Foundation Inflammatory Bowel Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
Christoph KleinDr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, Ludwig Maximilian University Munich, Munich, Germany; German Center for Child and Adolescent Health (DZKJ), Partner Site Munich, Munich, Germany.
Scott B SnapperDivision of Gastroenterology, Hepatology, & Nutrition, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; Division of Gastroenterology, Hepatology, and Endoscopy, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Jean-Laurent CasanovaLaboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, and Imagine Institute, Paris Cité University, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York; Department of Pediatrics, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris, Paris, France; Howard Hughes Medical Institute, New York, New York.
Raif GehaDivision of Immunology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
Edward HoffenbergDepartment of Pediatrics, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Dermot P B McGovernF. Widjaja Foundation Inflammatory Bowel Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
Eric SchadtDepartment of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
Daniel KotlarzDr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, Ludwig Maximilian University Munich, Munich, Germany; German Center for Child and Adolescent Health (DZKJ), Partner Site Munich, Munich, Germany; Institute of Translational Genomics, Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany. Electronic address: daniel.kotlarz@med.uni-muenchen.de.
Dali LiShanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China. Electronic address: dlli@bio.ecnu.edu.cn.
Aleixo M MuiseCell and Systems Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Departments of Pediatrics, Institute of Medical Science, and Biochemistry, University of Toronto, Toronto, Ontario, Canada. Electronic address: aleixo.muise@utoronto.ca.

Funding

COngenital Diarrhea and Enteropathy (PediCODE) Consortium and BioRepositoryRC2DK118640 · NIDDK · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI James Richard Goldenring, Izumi Kaji · 2019 to 2026
$14.8M
Identifying Immune and Epithelial Network Signatures in Very Early Onset Inflammatory Bowel DiseaseRC2DK122532 · NIDDK · BOSTON CHILDREN'S HOSPITAL · PI KLEIN, CHRISTOPH, MUISE, ALEIXO M · 2020 to 2024
$9.1M
NIDDK NIH HHS RC2 DK118640NIDDK NIH HHS RC2 DK122532
6 · The paper itself

Abstract

BACKGROUND &

aimsTumor 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.

methodsWe 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.

resultsRare 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

conclusionsWe establish BIRC3 deficiency as a cause of monogenic CD in both pediatric- and adult-onset patients and identify RIPK1 as a therapeutic target.

Indexed as

BIRC3cIAP2Monogenic IBDRIPK1

Identifiers

PMID42335979
PMCPMC13340323

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