Qi Li1, Cheng Hiang Lee2, Lauren A Peters3, Lucas A Mastropaolo4, Cornelia Thoeni1, Abdul Elkadri5, Tobias Schwerd6, Jun Zhu7, Bin Zhang7, Yongzhong Zhao7, Ke Hao7, Antonio Dinarzo7, Gabriel Hoffman7, Brian A Kidd7, Ryan Murchie1, Ziad Al Adham5, Conghui Guo4, Daniel Kotlarz8, Ernest Cutz9, Thomas D Walters1, Dror S Shouval10, Mark Curran11, Radu Dobrin11, Carrie Brodmerkel11, Scott B Snapper12, Christoph Klein8, John H Brumell13, Mingjing Hu2, Ralph Nanan2, Brigitte Snanter-Nanan2, Melanie Wong14, Francoise Le Deist15, Elie Haddad16, Chaim M Roifman17, Colette Deslandres18, Anne M Griffiths1, Kevin J Gaskin2, Holm H Uhlig6, Eric E Schadt7, Aleixo M Muise19. 1. 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. 2. 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. 3. 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. 4. Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada. 5. 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. 6. Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, University of Oxford and Department of Pediatrics, John Radcliffe Hospital, Oxford, UK. 7. 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. 8. Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany. 9. Division of Pathology, The Hospital for Sick Children, Toronto, Ontario, Canada. 10. Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts. 11. Janssen R&D, LLC, Spring House, Pennsylvania. 12. 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. 13. 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. 14. Immunology Department, The Children's Hospital at Westmead, Westmead, New South Wales, Australia. 15. Department of Microbiology and Immunology, CHU Sainte Justine and Department of Microbiology, Infectiology and Immunology, University of Montreal, Quebec, Canada. 16. Department of Pediatrics, CHU Sainte-Justine, Department of Microbiology, Infectiology and Immunology, University of Montreal, Quebec, Canada. 17. Division of Immunology, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Canada. 18. Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, CHU Sainte-Justine, Montreal, Quebec, Canada. 19. 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.
Abstract
BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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: Patrick Eldin; Laura Papon; Alexandra Oteiza; Emiliana Brocchi; T Glen Lawson; Nadir Mechti Journal: J Gen Virol Date: 2009-03 Impact factor: 3.891
Authors: Yvonne Zeissig; Britt-Sabina Petersen; Snezana Milutinovic; Esther Bosse; Gabriele Mayr; Kenneth Peuker; Jelka Hartwig; Andreas Keller; Martina Kohl; Martin W Laass; Susanne Billmann-Born; Heide Brandau; Alfred C Feller; Christoph Röcken; Martin Schrappe; Philip Rosenstiel; John C Reed; Stefan Schreiber; Andre Franke; Sebastian Zeissig Journal: Gut Date: 2014-02-26 Impact factor: 23.059
Authors: G T Ho; H M Lee; G Brydon; T Ting; N Hare; H Drummond; A G Shand; D C Bartolo; R G Wilson; M G Dunlop; I D Arnott; J Satsangi Journal: Am J Gastroenterol Date: 2009-02-17 Impact factor: 10.864
Authors: Yael Haberman; Timothy L Tickle; Phillip J Dexheimer; Mi-Ok Kim; Dora Tang; Rebekah Karns; Robert N Baldassano; Joshua D Noe; Joel Rosh; James Markowitz; Melvin B Heyman; Anne M Griffiths; Wallace V Crandall; David R Mack; Susan S Baker; Curtis Huttenhower; David J Keljo; Jeffrey S Hyams; Subra Kugathasan; Thomas D Walters; Bruce Aronow; Ramnik J Xavier; Dirk Gevers; Lee A Denson Journal: J Clin Invest Date: 2014-07-08 Impact factor: 14.808
Authors: Birte Zurek; Martina Proell; Roland N Wagner; Robert Schwarzenbacher; Thomas A Kufer Journal: Innate Immun Date: 2011-02-10 Impact factor: 2.680
Authors: Birte Zurek; Ida Schoultz; Andreas Neerincx; Luisa M Napolitano; Katharina Birkner; Eveline Bennek; Gernot Sellge; Maria Lerm; Germana Meroni; Johan D Söderholm; Thomas A Kufer Journal: PLoS One Date: 2012-07-19 Impact factor: 3.240
Authors: Andrea Di Pietro; Anna Kajaste-Rudnitski; Alexandra Oteiza; Lucia Nicora; Greg J Towers; Nadir Mechti; Elisa Vicenzi Journal: J Virol Date: 2013-02-13 Impact factor: 5.103
Authors: Ariella Cohain; Aparna A Divaraniya; Kuixi Zhu; Joseph R Scarpa; Andrew Kasarskis; Jun Zhu; Rui Chang; Joel T Dudley; Eric E Schadt Journal: Pac Symp Biocomput Date: 2017
Authors: Jodie Ouahed; Elizabeth Spencer; Daniel Kotlarz; Dror S Shouval; Matthew Kowalik; Kaiyue Peng; Michael Field; Leslie Grushkin-Lerner; Sung-Yun Pai; Athos Bousvaros; Judy Cho; Carmen Argmann; Eric Schadt; Dermot P B Mcgovern; Michal Mokry; Edward Nieuwenhuis; Hans Clevers; Fiona Powrie; Holm Uhlig; Christoph Klein; Aleixo Muise; Marla Dubinsky; Scott B Snapper Journal: Inflamm Bowel Dis Date: 2020-05-12 Impact factor: 5.325