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P695 A mutation in CTLA4 associated with early-onset Crohn's disease and autoimmunity

S. Zeissig*1, B.-S. Petersen2, M. Tomczak3, E. Melum4, E. Huc-Claustre1, S. Dougan3, J.K. Laerdahl5, B. Stade2, M. Forster2, S. Schreiber1, D. Weir6, A.M. Leichtner6, A. Franke2, R.S. Blumberg3

1Kiel University, Department of Internal Medicine I, Kiel, Germany, 2Christian-Albrechts-University Kiel, Institute of Clinical Molecular Biology, Kiel, Germany, 3Brigham and Women's Hospital, Division of Gastroenterology, Hepatology, and Endoscopy, Boston, United States, 4Oslo University Hospital, Norwegian PSC Research Center, Oslo, Norway, 5Oslo University Hospital, Department of Microbiology, Oslo, Norway, 6Boston Children’s Hospital, Division of Gastroenterology, Hepatology and Nutrition, Boston, United States


Host genetics regulate the susceptibility to inflammatory bowel disease (IBD). While the genetic basis of IBD is incompletely understood, rare Mendelian forms of IBD have been identified and provide critical insight into disease pathogenesis.


Exome sequencing and functional studies were applied to delineate the pathogenesis of disease in a family with early-onset Crohn's disease (CD) and autoimmunity.


We describe two half-siblings with severe, early-onset CD manifesting at the age of 7 and 13 years, who exhibited a complex immune-mediated syndrome consisting of intestinal inflammation, type I diabetes, demyelinating encephalopathy, fibrosing lung disease, and hematologic alterations. Exome sequencing of the two half-siblings, their mother and their fathers revealed a mutation shared by the siblings and the mother in the gene encoding cytotoxic T-lymphocyte associated protein 4 (CTLA-4), a co-inhibitory protein expressed by T cells, whose deficiency in mice and antibody-mediated blockade in humans is associated with intestinal inflammation and autoimmunity. CTL-4 Y60C affected an evolutionarily conserved residue in the immunoglobulin domain of CTLA-4, which was associated with reduced CTLA-4 dimerization, impaired cell surface expression, and abrogated binding of one of its ligands, the co-stimulatory protein CD80. Phenotypic and functional analyses of peripheral blood mononuclear cells of the affected son demonstrated an expanded CD4+ memory T cell population as well as increased T cell proliferation in vitro. The mother of the affected half-siblings shared the CTLA4 mutation and exhibited an expansion of CD4+ memory T cells but was asymptomatic. In studies to identify potential genetic modifiers explaining incomplete disease penetrance, exome sequencing revealed homozygosity of the mother for a common IL10 variant associated with increased IL-10 secretion (allele G of marker rs3024496), while both affected children were heterozygous for this variant.


Together, these results demonstrate that mutations in CTLA4 can provide the basis for Mendelian forms of early-onset CD. Incomplete penetrance of intestinal inflammation and autoimmunity in carriers of this CTLA4 mutation suggests the presence of additional genetic and/or environmental modifiers.