2. Academic Validation
  3. Mutations in tetratricopeptide repeat domain 7A result in a severe form of very early onset inflammatory bowel disease

Mutations in tetratricopeptide repeat domain 7A result in a severe form of very early onset inflammatory bowel disease

  • Gastroenterology. 2014 Apr;146(4):1028-39. doi: 10.1053/j.gastro.2014.01.015.
Yaron Avitzur 1,  Conghui Guo 2,  Lucas A Mastropaolo 2,  Ehsan Bahrami 3,  Hannah Chen 4,  Zhen Zhao 2,  Abdul Elkadri 5,  Sandeep Dhillon 2,  Ryan Murchie 2,  Ramzi Fattouh 2,  Hien Huynh 6,  Jennifer L Walker 7,  Paul W Wales 8,  Ernest Cutz 9,  Yoichi Kakuta 10,  Joel Dudley 11,  Jochen Kammermeier 12,  Fiona Powrie 13,  Neil Shah 12,  Christoph Walz 14,  Michaela Nathrath 15,  Daniel Kotlarz 3,  Jacek Puchaka 3,  Jonathan R Krieger 2,  Tomas Racek 3,  Thomas Kirchner 14,  Thomas D Walters 16,  John H Brumell 5,  Anne M Griffiths 16,  Nima Rezaei 17,  Parisa Rashtian 18,  Mehri Najafi 18,  Maryam Monajemzadeh 19,  Stephen Pelsue 7,  Dermot P B McGovern 10,  Holm H Uhlig 4,  Eric Schadt 11,  Christoph Klein 3,  Scott B Snapper 20,  Aleixo M Muise 21
Affiliations

Affiliations

  • 1 Group for Improvement of Intestinal Function and Treatment (GIFT), Hospital for Sick Children, Toronto, Ontario, Canada; 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 SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
  • 3 Department of Pediatrics, Dr von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany.
  • 4 Translational Gastroenterology Unit and Paediatric Gastroenterology, University of Oxford, Oxford, UK.
  • 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 Division of Pediatric Gastroenterology, Stollery Children's Hospital, Edmonton, Ontario, Canada.
  • 7 Department of Immunology and Molecular Biology, University of Southern Maine, Portland, Maine.
  • 8 Group for Improvement of Intestinal Function and Treatment (GIFT), Hospital for Sick Children, Toronto, Ontario, Canada.
  • 9 Division of Pathology, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • 10 F. Widjaja Foundation Inflammatory Bowel Disease Center and Immunobiology Research Institute at Cedars-Sinai Medical Center, Los Angeles, California.
  • 11 Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomics Sciences at Mount Sinai, New York, New York.
  • 12 Gastroenterology Department, Great Ormond Street Hospital, London, UK.
  • 13 Translational Gastroenterology Unit, Nuffield Department Clinical Medicine-Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford, UK.
  • 14 Institute for Pathology, Ludwig-Maximilians University, Munich, Germany.
  • 15 Department of Pediatric Oncology, Kassel and CCG Osteosarcoma, Helmholtz Center Munich, Munich, Germany.
  • 16 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.
  • 17 Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Molecular Immunology Research Center and Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
  • 18 Department of Pediatric Gastroenterology, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
  • 19 Department of Pathology, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
  • 20 Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Children's Hospital Boston, Massachusetts; Division of Gastroenterology and Hepatology, Brigham & Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts.
  • 21 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.
PMID: 24417819 DOI: 10.1053/j.gastro.2014.01.015
Abstract

Background & aims: Very early onset inflammatory bowel diseases (VEOIBD), including infant disorders, are a diverse group of diseases found in children younger than 6 years of age. They have been associated with several gene variants. Our aim was to identify the genes that cause VEOIBD.

Methods: We performed whole exome Sequencing of DNA from 1 infant with severe enterocolitis and her parents. Candidate gene mutations were validated in 40 pediatric patients and functional studies were carried out using intestinal samples and human intestinal cell lines.

Results: We identified compound heterozygote mutations in the Tetratricopeptide repeat domain 7 (TTC7A) gene in an infant from non-consanguineous parents with severe exfoliative apoptotic enterocolitis; we also detected TTC7A mutations in 2 unrelated families, each with 2 affected siblings. TTC7A interacts with EFR3 homolog B to regulate phosphatidylinositol 4-kinase at the plasma membrane. Functional studies demonstrated that TTC7A is expressed in human enterocytes. The mutations we identified in TTC7A result in either mislocalization or reduced expression of TTC7A. Phosphatidylinositol 4-kinase was found to co-immunoprecipitate with TTC7A; the identified TTC7A mutations reduced this binding. Knockdown of TTC7A in human intestinal-like cell lines reduced their adhesion, increased Apoptosis, and decreased production of phosphatidylinositol 4-phosphate.

Conclusions: In a genetic analysis, we identified loss of function mutations in TTC7A in 5 infants with VEOIBD. Functional studies demonstrated that the mutations cause defects in enterocytes and T cells that lead to severe apoptotic enterocolitis. Defects in the phosphatidylinositol 4-kinase-TTC7A-EFR3 homolog B pathway are involved in the pathogenesis of VEOIBD.

Keywords

Autoimmunity; IBD; Intestinal Atresia; Intestine.

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