1. The E3 ubiquitin ligase UBR5 interacts with TTC7A and may be associated with very early onset inflammatory bowel disease
- Author
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Scott B. Snapper, Qi Li, Christoph Klein, Neil Warner, Neel Dhingani, Sasha Jardine, Claudia Gonzaga-Jauregui, Daniel Kotlarz, Aleixo M. Muise, Conghui Guo, Jie Pan, Gabriella Leung, Víctor Manuel Navas-López, [Dhingani,N, Jardine,S, Muise,AM] Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada. [Dhingani,N, Guo,C, Pan,J, Li,Q, Warner,N, Leung,G, Muise,AM] SickKids Infammatory Bowel Disease Centre, Research Institute, Hospital for Sick Children, Toronto, ON, Canada. [Kotlarz,D, Klein,C] Department of Pediatrics, Dr. Von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany. [Gonzaga-Jauregui,C] Regeneron Genetics Center, Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA. [Snapper,SB] Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA. [Navas-López,VM] Pediatric Gastroenterology and Nutrition Unit, IBIMA, Hospital Regional Universitario de Málaga, Málaga, Spain. [Muise,AM] Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada. [Muise,AM] Department of Pediatrics, Institute of Medical Science, University of Toronto, Toronto, Canada. [Snapper,SB] Division of Gastroenterology, Brigham and Women’s Hospital, Boston, MA, USA., and AMM is funded by a Canada Research Chair (Tier 1) in Pediatric IBD, CIHR Foundation Grant and NIDDK (RC2DK118640) Grant. AMM, SBS, CK, DK are supported by the Leona M. and Harry B. Helmsley Charitable Trust. CK and DK are supported by the Collaborative Research Consortium SFB1054 project A05.
- Subjects
0301 basic medicine ,Male ,Enfermedades inflamatorias del intestino ,lcsh:Medicine ,Compound heterozygosity ,Inflammatory bowel disease ,Diseases::Digestive System Diseases::Gastrointestinal Diseases::Intestinal Diseases::Inflammatory Bowel Diseases [Medical Subject Headings] ,Unión proteica ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] ,0302 clinical medicine ,Age of Onset ,lcsh:Science ,Child ,Immunodeficiency ,Exome sequencing ,Multidisciplinary ,biology ,Intestinal atresia ,Gastroenterology ,Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Signal Transduction [Medical Subject Headings] ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins [Medical Subject Headings] ,Colitis ,3. Good health ,Ubiquitin ligase ,Ubiquitin-protein ligases ,Tetratricopeptide ,030220 oncology & carcinogenesis ,Niño ,Child, Preschool ,Protein Binding ,Signal Transduction ,Cell biology ,Ubiquitin-Protein Ligases ,Check Tags::Male [Medical Subject Headings] ,Inflammatory bowel diseases ,Article ,Amino acid sequence ,03 medical and health sciences ,Ubiquitina-proteína ligasas ,Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Protein Binding [Medical Subject Headings] ,medicine ,Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Ligases::Ubiquitin-Protein Ligase Complexes::Ubiquitin-Protein Ligases [Medical Subject Headings] ,Protein binding ,Humans ,Secuencia de aminoácidos ,Amino Acid Sequence ,Health Care::Health Care Quality, Access, and Evaluation::Quality of Health Care::Epidemiologic Factors::Age Factors::Age of Onset [Medical Subject Headings] ,Diseases::Digestive System Diseases::Gastrointestinal Diseases::Intestinal Diseases::Colonic Diseases::Colitis [Medical Subject Headings] ,Sequence Homology, Amino Acid ,business.industry ,lcsh:R ,Proteins ,medicine.disease ,Inflammatory Bowel Diseases ,030104 developmental biology ,Immunology ,biology.protein ,Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Molecular Structure::Amino Acid Sequence [Medical Subject Headings] ,lcsh:Q ,business ,Persons::Persons::Age Groups::Child::Child, Preschool [Medical Subject Headings] - Abstract
Very early onset inflammatory bowel disease (VEOIBD) denotes children with onset of IBD before six years of age. A number of monogenic disorders are associated with VEOIBD including tetratricopeptide repeat domain 7A (TTC7A) deficiency. TTC7A-deficiency is characterized by apoptotic colitis in milder cases with severe intestinal atresia and immunodeficiency in cases with complete loss of protein. We used whole exome sequencing in a VEOIBD patient presenting with colitis characterized by colonic apoptosis and no identified known VEOIBD variants, to identify compound heterozygous deleterious variants in the Ubiquitin protein ligase E3 component N-recognin 5 (UBR5) gene. Functional studies demonstrated that UBR5 co-immunoprecipitates with the TTC7A and the UBR5 variants had reduced interaction between UBR5 and TTC7A. Together this implicates UBR5 in regulating TTC7A signaling in VEOIBD patients with apoptotic colitis.
- Published
- 2019