title: Variants in TRIM22 That Affect NOD2 Signaling Are Associated With Very-Early-Onset Inflammatory Bowel Disease.
abstract: Severe forms of inflammatory bowel disease (IBD) that develop in very young children can be caused by variants in a single gene. We performed whole-exome sequence (WES) analysis to identify genetic factors that might cause granulomatous colitis and severe perianal disease, with recurrent bacterial and viral infections, in an infant of consanguineous parents.
  
  
  
  We performed targeted WES analysis of DNA collected from the patient and her parents. We validated our findings by a similar analysis of DNA from 150 patients with very-early-onset IBD not associated with known genetic factors analyzed in Toronto, Oxford, and Munich. We compared gene expression signatures in inflamed vs noninflamed intestinal and rectal tissues collected from patients with treatment-resistant Crohn's disease who participated in a trial of ustekinumab. We performed functional studies of identified variants in primary cells from patients and cell culture.
  
  
  
  We identified a homozygous variant in the tripartite motif containing 22 gene (TRIM22) of the patient, as well as in 2 patients with a disease similar phenotype. Functional studies showed that the variant disrupted the ability of TRIM22 to regulate nucleotide binding oligomerization domain containing 2 (NOD2)-dependent activation of interferon-beta signaling and nuclear factor-κB. Computational studies demonstrated a correlation between the TRIM22-NOD2 network and signaling pathways and genetic factors associated very early onset and adult-onset IBD. TRIM22 is also associated with antiviral and mycobacterial effectors and markers of inflammation, such as fecal calprotectin, C-reactive protein, and Crohn's disease activity index scores.
  
  
  
  In WES and targeted exome sequence analyses of an infant with severe IBD characterized by granulomatous colitis and severe perianal disease, we identified a homozygous variant of TRIM22 that affects the ability of its product to regulate NOD2. Combined computational and functional studies showed that the TRIM22-NOD2 network regulates antiviral and antibacterial signaling pathways that contribute to inflammation. Further study of this network could lead to new disease markers and therapeutic targets for patients with very early and adult-onset IBD.
authors.affiliation: SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.affiliation: Gastroenterology Department, The Children's Hospital at Westmead, Westmead, New South Wales, Australia; The James Fairfax Institute of Paediatric Nutrition, University of Sydney, New South Wales, Australia.
authors.forename: Cheng Hiang
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai and the Icahn Institute for Genomics and Multiscale Biology, New York, New York.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Peters
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Lucas A
authors.initials: LA
authors.lastname: Mastropaolo
authors.affiliation: SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Thoeni
authors.affiliation: SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Abdul
authors.initials: A
authors.lastname: Elkadri
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, University of Oxford and Department of Pediatrics, John Radcliffe Hospital, Oxford, UK.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schwerd
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai and the Icahn Institute for Genomics and Multiscale Biology, New York, New York.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai and the Icahn Institute for Genomics and Multiscale Biology, New York, New York.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai and the Icahn Institute for Genomics and Multiscale Biology, New York, New York.
authors.forename: Yongzhong
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai and the Icahn Institute for Genomics and Multiscale Biology, New York, New York.
authors.forename: Ke
authors.initials: K
authors.lastname: Hao
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai and the Icahn Institute for Genomics and Multiscale Biology, New York, New York.
authors.forename: Antonio
authors.initials: A
authors.lastname: Dinarzo
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai and the Icahn Institute for Genomics and Multiscale Biology, New York, New York.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Hoffman
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai and the Icahn Institute for Genomics and Multiscale Biology, New York, New York.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Kidd
authors.affiliation: SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Ryan
authors.initials: R
authors.lastname: Murchie
authors.affiliation: SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ziad
authors.initials: Z
authors.lastname: Al Adham
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Conghui
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kotlarz
authors.affiliation: Division of Pathology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Ernest
authors.initials: E
authors.lastname: Cutz
authors.affiliation: SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Walters
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Dror S
authors.initials: DS
authors.lastname: Shouval
authors.affiliation: Janssen R&D, LLC, Spring House, Pennsylvania.
authors.forename: Mark
authors.initials: M
authors.lastname: Curran
authors.affiliation: Janssen R&D, LLC, Spring House, Pennsylvania.
authors.forename: Radu
authors.initials: R
authors.lastname: Dobrin
authors.affiliation: Janssen R&D, LLC, Spring House, Pennsylvania.
authors.forename: Carrie
authors.initials: C
authors.lastname: Brodmerkel
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; Division of Gastroenterology and Hepatology, Brigham & Women's Hospital, Department of Medicine, Boston, Massachusetts.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Snapper
authors.affiliation: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Klein
authors.affiliation: SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: John H
authors.initials: JH
authors.lastname: Brumell
authors.affiliation: Gastroenterology Department, The Children's Hospital at Westmead, Westmead, New South Wales, Australia; The James Fairfax Institute of Paediatric Nutrition, University of Sydney, New South Wales, Australia.
authors.forename: Mingjing
authors.initials: M
authors.lastname: Hu
authors.affiliation: Gastroenterology Department, The Children's Hospital at Westmead, Westmead, New South Wales, Australia; The James Fairfax Institute of Paediatric Nutrition, University of Sydney, New South Wales, Australia.
authors.forename: Ralph
authors.initials: R
authors.lastname: Nanan
authors.affiliation: Gastroenterology Department, The Children's Hospital at Westmead, Westmead, New South Wales, Australia; The James Fairfax Institute of Paediatric Nutrition, University of Sydney, New South Wales, Australia.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Snanter-Nanan
authors.affiliation: Immunology Department, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
authors.forename: Melanie
authors.initials: M
authors.lastname: Wong
authors.affiliation: Department of Microbiology and Immunology, CHU Sainte Justine and Department of Microbiology, Infectiology and Immunology, University of Montreal, Quebec, Canada.
authors.forename: Francoise
authors.initials: F
authors.lastname: Le Deist
authors.affiliation: Department of Pediatrics, CHU Sainte-Justine, Department of Microbiology, Infectiology and Immunology, University of Montreal, Quebec, Canada.
authors.forename: Elie
authors.initials: E
authors.lastname: Haddad
authors.affiliation: Division of Immunology, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Chaim M
authors.initials: CM
authors.lastname: Roifman
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, CHU Sainte-Justine, Montreal, Quebec, Canada.
authors.forename: Colette
authors.initials: C
authors.lastname: Deslandres
authors.affiliation: SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Griffiths
authors.affiliation: Gastroenterology Department, The Children's Hospital at Westmead, Westmead, New South Wales, Australia; The James Fairfax Institute of Paediatric Nutrition, University of Sydney, New South Wales, Australia.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Gaskin
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, University of Oxford and Department of Pediatrics, John Radcliffe Hospital, Oxford, UK.
authors.forename: Holm H
authors.initials: HH
authors.lastname: Uhlig
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai and the Icahn Institute for Genomics and Multiscale Biology, New York, New York.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.affiliation: SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. Electronic address: aleixo.muise@utoronto.ca.
authors.forename: Aleixo M
authors.initials: AM
authors.lastname: Muise
mesh_terms: D017668:Age of Onset; D001315:Australia; D002478:Cells, Cultured; D019295:Computational Biology; D003241:Consanguinity; D003424:Crohn Disease / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D030541:Databases, Genetic; D004739:England; D059472:Exome; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005858:Germany; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D015778:Minor Histocompatibility Antigens / Q000235:genetics* / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism*; D009864:Ontario; D010375:Pedigree; D010641:Phenotype; D060066:Protein Interaction Maps; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction; D014162:Transfection; D000070584:Tripartite Motif Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D015778:Minor Histocompatibility Antigens; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D012097:Repressor Proteins; C094314:TRIM22 protein, human; D000070584:Tripartite Motif Proteins
keywords: Antiviral and Antibacterial Networks; NF-kB; VEOIBD
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