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.
We thank the patient and his family for participating in this study; B. Fleckenstein and M. Schmidt for generating and providing patient-derived T cell lines; and G. Superti-Furga, J. Bigenzahn for providing the inducible protein expression system used for Jurkat T cells and together with N. Serwas, C.D. Conde, A. Kalinichenko, K. Ackerman and R. Martins for critically reviewing the manuscript and providing comments. The research leading to these results was funded by the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013) / ERC grant agreement 310857 (K.B.), the Vienna Science and Technology Fund (WWTF) through project LS14-031 (J.B.H. and K.B.), an unrestricted research grant from Celgene Austria (U.J.), the National Institutes of Health (R01AI067946 to J.S.O.), Boehringer Ingelheim Fonds (R.P.), the Austrian Science Fund (FWF): Project M1809-B19 (K.L.W.), and the French Agence Nationale de la Recherche (ANR-13-BSV1-0031 to L.D.).
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Salzer E, Çaǧdaş D, Hons M, et al. RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics. Nature Immunology. 2016;17(12):1352-1360. doi:10.1038/ni.3575
Salzer, E., Çaǧdaş, D., Hons, M., Mace, E., Garncarz, W., Petronczki, O., … Boztug, K. (2016). RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics. Nature Immunology, 17(12), 1352–1360. https://doi.org/10.1038/ni.3575
Salzer, Elisabeth, Deniz Çaǧdaş, Miroslav Hons, Emily Mace, Wojciech Garncarz, Oezlem Petronczki, René Platzer, et al. “RASGRP1 Deficiency Causes Immunodeficiency with Impaired Cytoskeletal Dynamics.” Nature Immunology 17, no. 12 (2016): 1352–60. https://doi.org/10.1038/ni.3575.
E. Salzer et al., “RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics,” Nature Immunology, vol. 17, no. 12, pp. 1352–1360, 2016.
Salzer E, Çaǧdaş D, Hons M, Mace E, Garncarz W, Petronczki O, Platzer R, Pfajfer L, Bilic I, Ban S, Willmann K, Mukherjee M, Supper V, Hsu H, Banerjee P, Sinha P, Mcclanahan F, Zlabinger G, Pickl W, Gribben J, Stockinger H, Bennett K, Huppa J, Dupré L, Sanal Ö, Jäger U, Sixt MK, Tezcan I, Orange J, Boztug K. 2016. RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics. Nature Immunology. 17(12), 1352–1360.
Salzer, Elisabeth, et al. “RASGRP1 Deficiency Causes Immunodeficiency with Impaired Cytoskeletal Dynamics.” Nature Immunology, vol. 17, no. 12, Nature Publishing Group, 2016, pp. 1352–60, doi:10.1038/ni.3575.