RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics

Nat Immunol. 2016 Dec;17(12):1352-1360. doi: 10.1038/ni.3575.

Elisabeth Salzer ¹ ², Deniz Cagdas ³, Miroslav Hons ⁴, Emily M Mace ⁵, Wojciech Garncarz ¹ ², Özlem Yüce Petronczki ¹ ², René Platzer ⁶, Laurène Pfajfer ¹ ², Ivan Bilic ¹, Sol A Ban ¹, Katharina L Willmann ¹, Malini Mukherjee ⁵, Verena Supper ⁶, Hsiang Ting Hsu ⁵, Pinaki P Banerjee ⁵, Papiya Sinha ⁵, Fabienne McClanahan ⁷, Gerhard J Zlabinger ⁸, Winfried F Pickl ⁹, John G Gribben ⁷, Hannes Stockinger ⁶, Keiryn L Bennett ¹, Johannes B Huppa ⁶, Loïc Dupré ¹ ² ¹⁰, Özden Sanal ³, Ulrich Jäger ¹¹, Michael Sixt ⁴, Ilhan Tezcan ³, Jordan S Orange ⁵, Kaan Boztug ¹ ² ¹² ¹³

Affiliations

1 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
2 Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
3 Section of Pediatric Immunology, Hacettepe University, Ihsan Dogramaci Children's Hospital, Ankara, Turkey.
4 Institute of Science and Technology Austria, Klosterneuburg, Austria.
5 Center for Human Immunobiology, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA.
6 Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
7 Centre for Haemato-Oncology, Barts Cancer Institute - a CR-UK Centre of Excellence, Queen Mary University of London, London, UK.
8 Institute of Immunology, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
9 Christian Doppler Laboratory for Immunomodulation and Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
10 Centre de Physiopathologie de Toulouse Purpan (CPTP), INSERM, UMR1043, Toulouse Purpan University Hospital, Toulouse, France.
11 Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.
12 Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
13 St. Anna Kinderspital and Children's Cancer Research Institute, Department of Pediatrics, Medical University of Vienna, Vienna, Austria.

PMID: 27776107 DOI: 10.1038/ni.3575

Abstract

RASGRP1 is an important guanine nucleotide exchange factor and activator of the RAS-MAPK pathway following T cell antigen receptor (TCR) signaling. The consequences of RASGRP1 mutations in humans are unknown. In a patient with recurrent Bacterial and viral infections, born to healthy consanguineous parents, we used homozygosity mapping and exome Sequencing to identify a biallelic stop-gain variant in RASGRP1. This variant segregated perfectly with the disease and has not been reported in genetic databases. RASGRP1 deficiency was associated in T cells and B cells with decreased phosphorylation of the extracellular-signal-regulated serine kinase ERK, which was restored following expression of wild-type RASGRP1. RASGRP1 deficiency also resulted in defective proliferation, activation and motility of T cells and B cells. RASGRP1-deficient natural killer (NK) cells exhibited impaired cytotoxicity with defective granule convergence and actin accumulation. Interaction proteomics identified the dynein LIGHT chain DYNLL1 as interacting with RASGRP1, which links RASGRP1 to cytoskeletal dynamics. RASGRP1-deficient cells showed decreased activation of the GTPase RhoA. Treatment with lenalidomide increased RhoA activity and reversed the migration and activation defects of RASGRP1-deficient lymphocytes.

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