title: Mutations in tetratricopeptide repeat domain 7A result in a severe form of very early onset inflammatory bowel disease.
abstract: OBJECTIVE
  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.
authors.affiliation: 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.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Avitzur
authors.affiliation: SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Conghui
authors.initials: C
authors.lastname: Guo
authors.affiliation: SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Lucas A
authors.initials: LA
authors.lastname: Mastropaolo
authors.affiliation: Department of Pediatrics, Dr von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Ehsan
authors.initials: E
authors.lastname: Bahrami
authors.affiliation: Translational Gastroenterology Unit and Paediatric Gastroenterology, University of Oxford, Oxford, UK.
authors.forename: Hannah
authors.initials: H
authors.lastname: Chen
authors.affiliation: SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhao
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: SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Dhillon
authors.affiliation: SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, 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.
authors.forename: Ramzi
authors.initials: R
authors.lastname: Fattouh
authors.affiliation: Division of Pediatric Gastroenterology, Stollery Children's Hospital, Edmonton, Ontario, Canada.
authors.forename: Hien
authors.initials: H
authors.lastname: Huynh
authors.affiliation: Department of Immunology and Molecular Biology, University of Southern Maine, Portland, Maine.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Walker
authors.affiliation: Group for Improvement of Intestinal Function and Treatment (GIFT), Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Wales
authors.affiliation: Division of Pathology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Ernest
authors.initials: E
authors.lastname: Cutz
authors.affiliation: F. Widjaja Foundation Inflammatory Bowel Disease Center and Immunobiology Research Institute at Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Kakuta
authors.affiliation: Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomics Sciences at Mount Sinai, New York, New York.
authors.forename: Joel
authors.initials: J
authors.lastname: Dudley
authors.affiliation: Gastroenterology Department, Great Ormond Street Hospital, London, UK.
authors.forename: Jochen
authors.initials: J
authors.lastname: Kammermeier
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department Clinical Medicine-Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Powrie
authors.affiliation: Gastroenterology Department, Great Ormond Street Hospital, London, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Shah
authors.affiliation: Institute for Pathology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Walz
authors.affiliation: Department of Pediatric Oncology, Kassel and CCG Osteosarcoma, Helmholtz Center Munich, Munich, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Nathrath
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: Department of Pediatrics, Dr von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Jacek
authors.initials: J
authors.lastname: Puchaka
authors.affiliation: SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Krieger
authors.affiliation: Department of Pediatrics, Dr von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Tomas
authors.initials: T
authors.lastname: Racek
authors.affiliation: Institute for Pathology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kirchner
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: 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: John H
authors.initials: JH
authors.lastname: Brumell
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: 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.
authors.forename: Nima
authors.initials: N
authors.lastname: Rezaei
authors.affiliation: Department of Pediatric Gastroenterology, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Parisa
authors.initials: P
authors.lastname: Rashtian
authors.affiliation: Department of Pediatric Gastroenterology, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Mehri
authors.initials: M
authors.lastname: Najafi
authors.affiliation: Department of Pathology, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Maryam
authors.initials: M
authors.lastname: Monajemzadeh
authors.affiliation: Department of Immunology and Molecular Biology, University of Southern Maine, Portland, Maine.
authors.forename: Stephen
authors.initials: S
authors.lastname: Pelsue
authors.affiliation: F. Widjaja Foundation Inflammatory Bowel Disease Center and Immunobiology Research Institute at Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Dermot P B
authors.initials: DP
authors.lastname: McGovern
authors.affiliation: Translational Gastroenterology Unit and Paediatric Gastroenterology, University of Oxford, Oxford, UK.
authors.forename: Holm H
authors.initials: HH
authors.lastname: Uhlig
authors.affiliation: Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomics Sciences at Mount Sinai, New York, New York.
authors.forename: Eric
authors.initials: E
authors.lastname: Schadt
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: 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.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Snapper
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: D019870:1-Phosphatidylinositol 4-Kinase / Q000378:metabolism; D017668:Age of Onset; D017209:Apoptosis; D002448:Cell Adhesion; D002460:Cell Line; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004760:Enterocolitis / Q000235:genetics; D020895:Enterocytes / Q000378:metabolism / Q000473:pathology; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015212:Inflammatory Bowel Diseases / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D007409:Intestinal Atresia / Q000235:genetics; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011379:Prognosis; D011485:Protein Binding; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D012720:Severity of Illness Index; D015398:Signal Transduction; D014162:Transfection
chemical_list: D011506:Proteins; C583818:TTC7A protein, human; D019870:1-Phosphatidylinositol 4-Kinase
keywords: Autoimmunity; IBD; Intestinal Atresia; Intestine