title: Early-onset Crohn's disease and autoimmunity associated with a variant in CTLA-4.
abstract: OBJECTIVE
  IBD is a group of complex, systemic disorders associated with intestinal inflammation and extraintestinal manifestations. Recent studies revealed Mendelian forms of IBD, which contributed significantly to our understanding of disease pathogenesis and the heritability of IBD.
  
  
  METHODS
  We performed exome sequencing in a family with Crohn's disease (CD) and severe autoimmunity, analysed immune cell phenotype and function in affected and non-affected individuals, and performed in silico and in vitro analyses of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) structure and function.
  
  
  RESULTS
  A novel missense variant was identified in CTLA4 encoding CTLA-4, a coinhibitory protein expressed by T cells and required for regulation of T cell activation. The residue affected by the mutation, CTLA-4 Tyr60, is evolutionarily highly conserved, and the identified Y60C variant is predicted to affect protein folding and structural stability and demonstrated to cause impaired CTLA-4 dimerisation and CD80 binding. Intestinal inflammation and autoimmunity in carriers of CTLA-4 Y60C exhibit incomplete penetrance with a spectrum of clinical presentations ranging from asymptomatic carrier status to fatal autoimmunity and intestinal inflammation. In a clinically affected CTLA-4 Y60C carrier, T cell proliferation was increased in vitro and associated with an increased ratio of memory to naive T cells in vivo, consistent with impaired regulation of T cell activation.
  
  
  CONCLUSIONS
  Our results support the concept that variants in CTLA4 provide the basis for a novel Mendelian form of early-onset CD associated with systemic autoimmunity. Incomplete penetrance of autoimmunity further indicates the presence of other genetic and/or environmental modifiers.
authors.affiliation: Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Kiel, Germany Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zeissig
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Britt-Sabina
authors.initials: BS
authors.lastname: Petersen
authors.affiliation: Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michal
authors.initials: M
authors.lastname: Tomczak
authors.affiliation: Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway K.G. Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Espen
authors.initials: E
authors.lastname: Melum
authors.affiliation: Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Kiel, Germany.
authors.forename: Emilie
authors.initials: E
authors.lastname: Huc-Claustre
authors.affiliation: Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Stephanie K
authors.initials: SK
authors.lastname: Dougan
authors.affiliation: Department of Microbiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway Bioinformatics Core Facility, Department of Informatics, University of Oslo, Oslo, Norway.
authors.forename: Jon K
authors.initials: JK
authors.lastname: Laerdahl
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Stade
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Forster
authors.affiliation: Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Kiel, Germany Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Dascha
authors.initials: D
authors.lastname: Weir
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Leichtner
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Blumberg
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics*; D018122:B7-1 Antigen / Q000378:metabolism; D018791:CD4 Lymphocyte Count; D060908:CTLA-4 Antigen / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics; D002648:Child; D003424:Crohn Disease / Q000235:genetics* / Q000276:immunology*; D004252:DNA Mutational Analysis; D003922:Diabetes Mellitus, Type 1 / Q000150:complications; D019281:Dimerization; D059472:Exome; D005260:Female; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics; D020125:Mutation, Missense; D010375:Pedigree; D019683:Penetrance; D055503:Protein Multimerization / Q000235:genetics; D017422:Sequence Analysis, DNA; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism*; D055815:Young Adult
chemical_list: D018122:B7-1 Antigen; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human
keywords: CROHN'S DISEASE; GENE MUTATION; IMMUNOLOGY; IMMUNOREGULATION