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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 (2018): Novel Mutations in RASGRP1 are Associated with Immunodeficiency, Immune Dysregulation, and EBV-Induced Lymphoma. In: Journal of Clinical Immunology, Vol. 38, No. 6: pp. 699-710
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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. 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. 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) V beta repertoires, and increased frequencies of TCR gamma delta cells. TCR gamma repertoire diversity was significantly reduced with a remarkable clonal expansion. 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.