Novel pathogenic CTLA4 missense variant associated with autoimmune enteropathy and systemic immune dysregulation.
This human observational report identifies a novel germline CTLA4 p.Phe56Cys loss-of-function variant in a patient with adolescent-onset autoimmune enteropathy and early-onset gastric malignancy, demonstrates impaired CTLA4 dimerization and CD80/CD86 binding, and reports symptomatic improvement with partial Treg restoration after abatacept.
Open original publication →What the AI sees
This human observational report identifies a novel germline CTLA4 p.Phe56Cys loss-of-function variant in a patient with adolescent-onset autoimmune enteropathy and early-onset gastric malignancy, demonstrates impaired CTLA4 dimerization and CD80/CD86 binding, and reports symptomatic improvement with partial Treg restoration after abatacept.
Research significance
The record provides patient-level evidence that abatacept was associated with partial immunologic and symptomatic improvement; it supports, but does not establish, the hypothesis that molecularly confirmed CTLA4 haploinsufficiency can guide CTLA4-pathway replacement therapy in selected patients with refractory immune dysregulation.
Source abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.