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01-08-2018 | Original Article

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

Authors: Ido Somekh, Benjamin Marquardt, Yanshan Liu, Meino Rohlfs, Sebastian Hollizeck, Musa Karakukcu, Ekrem Unal, Ebru Yilmaz, Turkan Patiroglu, Murat Cansever, Shirly Frizinsky, Vicktoria Vishnvenska-Dai, Erez Rechavi, Tali Stauber, Amos J. Simon, Atar Lev, Christoph Klein, Daniel Kotlarz, Raz Somech

Published in: Journal of Clinical Immunology | Issue 6/2018

Abstract

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.

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Title: Novel Mutations in RASGRP1 are Associated with Immunodeficiency, Immune Dysregulation, and EBV-Induced Lymphoma
Authors: Ido Somekh
Benjamin Marquardt
Yanshan Liu
Meino Rohlfs
Sebastian Hollizeck
Musa Karakukcu
Ekrem Unal
Ebru Yilmaz
Turkan Patiroglu
Murat Cansever
Shirly Frizinsky
Vicktoria Vishnvenska-Dai
Erez Rechavi
Tali Stauber
Amos J. Simon
Atar Lev
Christoph Klein
Daniel Kotlarz
Raz Somech
Publication date: 01-08-2018
Publisher: Springer US
Published in: Journal of Clinical Immunology / Issue 6/2018
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-018-0533-8

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Purpose

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Conclusions

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