title: RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics.
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.
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
authors: Elisabeth
authors: E
authors: Salzer
authors: Section of Pediatric Immunology, Hacettepe University, Ihsan Dogramaci Children's Hospital, Ankara, Turkey.
authors: Deniz
authors: D
authors: Cagdas
authors: Institute of Science and Technology Austria, Klosterneuburg, Austria.
authors: Miroslav
authors: M
authors: Hons
authors: Center for Human Immunobiology, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA.
authors: Emily M
authors: EM
authors: Mace
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
authors: Wojciech
authors: W
authors: Garncarz
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
authors: Özlem Yüce
authors: ÖY
authors: Petronczki
authors: Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
authors: René
authors: R
authors: Platzer
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
authors: Laurène
authors: L
authors: Pfajfer
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors: Ivan
authors: I
authors: Bilic
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors: Sol A
authors: SA
authors: Ban
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors: Katharina L
authors: KL
authors: Willmann
authors: Center for Human Immunobiology, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA.
authors: Malini
authors: M
authors: Mukherjee
authors: Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
authors: Verena
authors: V
authors: Supper
authors: Center for Human Immunobiology, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA.
authors: Hsiang Ting
authors: HT
authors: Hsu
authors: Center for Human Immunobiology, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA.
authors: Pinaki P
authors: PP
authors: Banerjee
authors: Center for Human Immunobiology, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA.
authors: Papiya
authors: P
authors: Sinha
authors: Centre for Haemato-Oncology, Barts Cancer Institute - a CR-UK Centre of Excellence, Queen Mary University of London, London, UK.
authors: Fabienne
authors: F
authors: McClanahan
authors: Institute of Immunology, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
authors: Gerhard J
authors: GJ
authors: Zlabinger
authors: Christian Doppler Laboratory for Immunomodulation and Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
authors: Winfried F
authors: WF
authors: Pickl
authors: Centre for Haemato-Oncology, Barts Cancer Institute - a CR-UK Centre of Excellence, Queen Mary University of London, London, UK.
authors: John G
authors: JG
authors: Gribben
authors: Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
authors: Hannes
authors: http://orcid.org/0000-0001-6404-4430
authors: H
authors: Stockinger
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors: Keiryn L
authors: KL
authors: Bennett
authors: Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
authors: Johannes B
authors: JB
authors: Huppa
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.|Centre de Physiopathologie de Toulouse Purpan (CPTP), INSERM, UMR1043, Toulouse Purpan University Hospital, Toulouse, France.
authors: Loïc
authors: L
authors: Dupré
authors: Section of Pediatric Immunology, Hacettepe University, Ihsan Dogramaci Children's Hospital, Ankara, Turkey.
authors: Özden
authors: Ö
authors: Sanal
authors: Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.
authors: Ulrich
authors: U
authors: Jäger
authors: Institute of Science and Technology Austria, Klosterneuburg, Austria.
authors: Michael
authors: M
authors: Sixt
authors: Section of Pediatric Immunology, Hacettepe University, Ihsan Dogramaci Children's Hospital, Ankara, Turkey.
authors: Ilhan
authors: I
authors: Tezcan
authors: Center for Human Immunobiology, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA.
authors: Jordan S
authors: JS
authors: Orange
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.|Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.|St. Anna Kinderspital and Children's Cancer Research Institute, Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
authors: Kaan
authors: K
authors: Boztug
mesh_terms: D000199:Actins / Q000378:metabolism*; D000293:Adolescent; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002648:Child; D003599:Cytoskeleton / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D004398:Dyneins / Q000378:metabolism; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics; D007153:Immunologic Deficiency Syndromes / Q000188:drug therapy / Q000235:genetics*; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D000077269:Lenalidomide; D008297:Male; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D034741:RNA, Small Interfering / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000199:Actins; D020533:Angiogenesis Inhibitors; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; C491790:RASGRP1 protein, human; D034741:RNA, Small Interfering; D013792:Thalidomide; D004398:Dyneins; D000077269:Lenalidomide