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| Home > Publications database > Novel pathogenic CTLA4 missense variant associated with autoimmune enteropathy and systemic immune dysregulation. |
| Journal Article | DKFZ-2026-01978 |
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2026
Frontiers Media
Lausanne
Abstract: Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA4) haploinsufficiency is a rare monogenic immunodysregulatory disorder that can affect multiple organ systems, leading to a combination of autoimmunity, immunodeficiency, and lymphoproliferation. It is caused by heterozygous germline mutations of CTLA4, yet the structure-function relationships underlying individual pathogenic variants remain incompletely understood.We performed whole-exome sequencing on a patient with adolescent-onset autoimmune enteropathy, early-onset gastric malignancy and multisystem comorbidities, who was initially misdiagnosed with Crohn's disease and refractory to multiple biologics. Functional assays assessed CTLA4 dimerization and CD80/CD86 binding capacity. Peripheral blood immunophenotyping was conducted using CyTOF and flow cytometry. Intestinal histopathology was evaluated by immunohistochemistry. The patient subsequently received targeted therapy with abatacept.A novel heterozygous missense variant in CTLA4 (c.167T>G, p.Phe56Cys) was identified. Functional assays demonstrated that this variant impairs CTLA4 protein dimerization and its binding capacity to CD80/CD86, establishing loss-of-function as the molecular basis of pathogenicity. Comprehensive peripheral blood immunophenotyping by CyTOF revealed a broad adaptive immune dysregulation landscape, characterized by depletion of regulatory T cells (Tregs), γδ T cells, and CD161+ cytotoxic-like CD8+ T cells. Flow cytometry confirmed reduction in CD4+CD25+Foxp3+ Treg cells along with decreased CTLA4 expression. Intestinal histopathology showed crypt apoptosis with T cell-predominant infiltration, distinct from classic inflammatory bowel disease. Notably, targeted therapy with abatacept partially restored Treg frequency and alleviated clinical symptoms.These findings identify p.Phe56Cys as a novel loss-of-function CTLA4 variant that disrupts protein dimerization and ligand binding, expanding the mechanistic understanding of CTLA4 haploinsufficiency and supporting genetic screening in patients with refractory autoimmune enteropathy and early-onset gastric malignancy.
Keyword(s): CTLA4 haploinsufficiency ; abatacept ; autoimmune enteropathy ; primary immunodeficiencies ; regulatory T cells
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