{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T10:59:07Z","timestamp":1793876347462,"version":"4.7.0"},"reference-count":55,"publisher":"BMJ","issue":"12","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["Gut"],"accepted":{"date-parts":[[2014,10,9]]},"published-print":{"date-parts":[[2015,12]]},"abstract":"<jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Design<\/jats:title>\n                  <jats:p>We performed exome sequencing in a family with Crohn\u2019s disease (CD) and severe autoimmunity, analysed immune cell phenotype and function in affected and non-affected individuals, and performed <jats:italic>in silico<\/jats:italic> and in vitro analyses of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) structure and function.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>A novel missense variant was identified in <jats:italic>CTLA4<\/jats:italic> 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 <jats:italic>in vitro<\/jats:italic> and associated with an increased ratio of memory to naive T cells <jats:italic>in vivo<\/jats:italic>, consistent with impaired regulation of T cell activation.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our results support the concept that variants in <jats:italic>CTLA4<\/jats:italic> 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.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/gutjnl-2014-308541","type":"journal-article","created":{"date-parts":[[2014,11,3]],"date-time":"2014-11-03T23:52:57Z","timestamp":1415058777000},"page":"1889-1897","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":128,"title":["Early-onset Crohn\u2019s disease and autoimmunity associated with a variant in CTLA-4"],"prefix":"10.1136","volume":"64","author":[{"given":"Sebastian","family":"Zeissig","sequence":"first","affiliation":[{"name":"Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Kiel, Germany"},{"name":"Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Britt-Sabina","family":"Petersen","sequence":"additional","affiliation":[{"name":"Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Tomczak","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Espen","family":"Melum","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA"},{"name":"Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway"},{"name":"K.G. 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