A novel homozygous mutation in RASGRP1 that predisposes to immune dysregulation and immunodeficiency associated with uncontrolled Epstein-Barr virus-induced B cell proliferation
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Academic Press Inc.
Abstract
Background: RASGRP1-deficiency results in an immune dysregulation and immunodeficiency that manifest as autoimmunity, lymphoproliferation, lymphopenia, defective T cell function, and increased incidence of Epstein-Bar Virus infections and lymphomas. Objective: To investigate the mechanism of autoimmune hemolytic anemia and infections in a male patient of consanguineous parents from Lebanon. Methods: Genetic diagnosis was obtained using next generation and Sanger sequencing. Protein expression and phosphorylation were determined by immunoblotting. T and B cell development and function were studied by flow cytometry. Cytokine and immunoglobulin secretions were quantified by enzyme-linked immunosorbent assay. Results: The patient suffered from severe lymphopenia especially affecting the T cell compartment. Genetic analysis revealed a homozygous insertion of adenine at position 1396_1397 in RASGRP1 that abolished protein expression and downstream Ras signaling. T cells from the patient showed severe activation defects resulting in uncontrolled Epstein-Bar Virus-induced B cell proliferation. B cells from the patient were normal. Conclusion: This report expands the spectrum of mutations in patients with RasGRP1 deficiency, and provides evidence for the important role RasGRP1 plays in the ability of T cells to control Epstein-Bar Virus-induced B cell proliferation. Clinical implications: Following diagnosis, the patient will be maintained on oral valganciclovir and monitored regularly for Epstein-Bar Virus infections to avoid the development of Epstein-Bar Virus- induced B cell lymphoma. He is also candidate for hematopoietic stem cell transplantation. © 2023 Elsevier Inc.
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Epstein-bar virus infections, Immune dysregulation, Immunodeficiency, Rasgrp1 deficiency, T cell function, Cell proliferation, Dna-binding proteins, Epstein-barr virus infections, Guanine nucleotide exchange factors, Herpesvirus 4, human, Humans, Immunologic deficiency syndromes, Lymphopenia, Male, Mutation, Antibiotic agent, Cd3 antigen, Cd4 antigen, Cd40 ligand, Cd45ra antigen, Cd69 antigen, Cd8 antigen, Chemokine receptor ccr7, Cytokine, F actin, Gamma interferon, Genomic dna, Guanine nucleotide, Immunoglobulin, Immunoglobulin a, Immunoglobulin m, Interleukin 17, Lysosome associated membrane protein 1, Mycophenolate mofetil, Phorbol 13 acetate 12 myristate, Platelet endothelial cell adhesion molecule 1, Prednisone, Ras guanyl nucleotide releasing protein, Rituximab, Transcription factor foxp3, Unclassified drug, Dna binding protein, Guanine nucleotide exchange factor, Rasgrp1 protein, human, Achilles tendon rupture, Adolescent, Apoptosis assay, Article, Autoimmune hemolytic anemia, B lymphocyte, Basophil, Biochemical analysis, Body weight, Cd4+ t lymphocyte, Cd8+ t lymphocyte, Cell compartmentalization, Cell count, Cell maturation, Clinical article, Clinical feature, Colitis, Consanguineous marriage, Controlled study, Coombs test, Degranulation assay, Developmental delay, Disease severity, Eosinophil, Epstein barr virus, Epstein barr virus infection, Erythrocyte, Evans syndrome, Exploratory laparotomy, Female, First trimester pregnancy, Flow cytometry, Gene mutation, Genetic analysis, Genetic screening, Genetic susceptibility, High throughput sequencing, Homozygote, Human, Human cell, Immunoblotting, Immunoglobulin blood level, Immunoglobulin production, Immunophenotyping, Laparotomy, Lebanon, Leukocyte, Limit of quantitation, Lung infection, Lymphocyte function, Lymphocyte subpopulation, Lymphocytopenia, Lymphoproliferative disease, Memory cell, Mental deficiency, Natural killer cell, Neutrophil, Peripheral blood mononuclear cell, Polymerization, Protein expression, Protein phosphorylation, Regulatory t lymphocyte, Sanger sequencing, Skin infection, Small intestine obstruction, Small intestine resection, Splenic vein, Spontaneous abortion, Superior mesenteric vein, T lymphocyte, T lymphocyte activation, Thrombocytopenia, Upper respiratory tract infection, Upregulation, Vein thrombosis, Complication, Genetics, Immune deficiency, Metabolism