Novel Mutations in RASGRP1 are Associated with Immunodeficiency, Immune Dysregulation, and EBV-Induced Lymphoma

• Published in: Journal of clinical immunology 2018-08, Vol.38 (6), p.699-710
• Main Authors: Somekh, Ido, Marquardt, Benjamin, Liu, Yanshan, Rohlfs, Meino, Hollizeck, Sebastian, Karakukcu, Musa, Unal, Ekrem, Yilmaz, Ebru, Patiroglu, Turkan, Cansever, Murat, Frizinsky, Shirly, Vishnvenska-Dai, Vicktoria, Rechavi, Erez, Stauber, Tali, Simon, Amos J., Lev, Atar, Klein, Christoph, Kotlarz, Daniel, Somech, Raz
• Format: Article
• Language: English
• Subjects: Autoimmune diseases; Autoimmunity; B-cell lymphoma; Biomedical and Life Sciences; Biomedicine; CD4 antigen; Ectopic expression; Epstein-Barr virus; Genetic screening; Guanosine triphosphatases; Hematopoietic stem cells; Immunoblotting; Immunodeficiency; Immunology; Infectious Diseases; Internal Medicine; Lymphocytes; Lymphocytes B; Lymphoma; Lymphopenia; Medical Microbiology; Mutation; Original Article; Patients; Primary immunodeficiencies; Protein deficiency; Ras protein; Stem cell transplantation; T cell receptors
• ISSN: 0271-9142; 1573-2592
• DOI: 10.1007/s10875-018-0533-8

Purpose RAS guanyl-releasing protein 1 (RASGRP1) deficiency has recently been shown to cause a primary immunodeficiency (PID) characterized by CD4 + T cell lymphopenia and Epstein-Barr virus (EBV)-associated B cell lymphoma. Our report of three novel patients widens the scope of RASGRP1 deficiency by providing new clinical and immunological insights on autoimmunity, immune cell development, and predisposition to lymphoproliferative disease. Methods One patient of Turkish origin (P1) and two Palestinian patients (P2, P3) were evaluated for immunodeficiency. To decipher the molecular cause of disease, whole exome sequencing was conducted. Identified mutations were validated by immunological and biochemical assays. Results We report three patients presenting with similar clinical characteristics of immunodeficiency and EBV-associated lymphoproliferative disease. In addition, P2 and P3 exhibited overt autoimmune manifestations. Genetic screening identified two novel loss-of-function mutations in RASGRP1 . Immunoblotting and active Ras pull-down assays confirmed perturbed ERK1/2 signaling and reduced Ras-GTPase activity in heterologous Jurkat cells with ectopic expression of RASGRP1 mutants. All three patients had CD4 + T cell lymphopenia. P2 and P3 showed decreased mitogen-induced lymphocyte proliferation, reduced T cell receptor excision circles, abnormal T cell receptor (TCR) Vβ repertoires, and increased frequencies of TCRγδ cells. TCR gamma repertoire diversity was significantly reduced with a remarkable clonal expansion. Conclusions RASGRP1 deficiency is associated with life-threatening immune dysregulation, severe autoimmune manifestations, and susceptibility to EBV-induced B cell malignancies. Early diagnosis is critical and hematopoietic stem cell transplantation might be considered as curative treatment.