RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics

Nat Immunol. 2016 Dec;17(12):1352-1360. doi: 10.1038/ni.3575. Epub 2016 Oct 24.


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.

Publication types

  • Case Reports

MeSH terms

  • Actins / metabolism*
  • Adolescent
  • Angiogenesis Inhibitors / pharmacology
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / immunology*
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • Child
  • Cytoskeleton / metabolism*
  • Cytotoxicity, Immunologic / genetics
  • DNA Mutational Analysis
  • DNA-Binding Proteins / genetics*
  • Dyneins / metabolism
  • Female
  • Guanine Nucleotide Exchange Factors / genetics*
  • HEK293 Cells
  • Humans
  • Immunoglobulin Class Switching / genetics
  • Immunologic Deficiency Syndromes / drug therapy
  • Immunologic Deficiency Syndromes / genetics*
  • Jurkat Cells
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology*
  • Lenalidomide
  • Male
  • Mutation / genetics
  • Pedigree
  • RNA, Small Interfering / genetics
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • Thalidomide / analogs & derivatives
  • Thalidomide / pharmacology


  • Actins
  • Angiogenesis Inhibitors
  • DNA-Binding Proteins
  • Guanine Nucleotide Exchange Factors
  • RASGRP1 protein, human
  • RNA, Small Interfering
  • Thalidomide
  • Dyneins
  • Lenalidomide