RT Journal Article
SR Electronic
T1 Early-onset Crohn’s disease and autoimmunity associated with a variant in CTLA-4
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 1889
OP 1897
DO 10.1136/gutjnl-2014-308541
VO 64
IS 12
A1 Zeissig, Sebastian
A1 Petersen, Britt-Sabina
A1 Tomczak, Michal
A1 Melum, Espen
A1 Huc-Claustre, Emilie
A1 Dougan, Stephanie K
A1 Laerdahl, Jon K
A1 Stade, Björn
A1 Forster, Michael
A1 Schreiber, Stefan
A1 Weir, Dascha
A1 Leichtner, Alan M
A1 Franke, Andre
A1 Blumberg, Richard S
YR 2015
UL http://gut.bmj.com/content/64/12/1889.abstract
AB 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.Design 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.