2. Academic Validation
  3. RASGRP1 mutation in autoimmune lymphoproliferative syndrome-like disease

RASGRP1 mutation in autoimmune lymphoproliferative syndrome-like disease

  • J Allergy Clin Immunol. 2018 Aug;142(2):595-604.e16. doi: 10.1016/j.jaci.2017.10.026.
Huawei Mao 1,  Wanling Yang 2,  Sylvain Latour 3,  Jing Yang 2,  Sarah Winter 3,  Jian Zheng 4,  Ke Ni 4,  Minmin Lv 5,  Chenjing Liu 6,  Hongmei Huang 6,  Koon-Wing Chan 4,  Pamela Pui-Wah Lee 2,  Wenwei Tu 2,  Alain Fischer 7,  Yu-Lung Lau 8
Affiliations

Affiliations

  • 1 Department of Paediatrics, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China; Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China; Shenzhen Engineering Laboratory of Primary Immunodeficiency Diagnosis and Therapy, Shenzhen, China. Electronic address: [email protected].
  • 2 Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China; Shenzhen Engineering Laboratory of Primary Immunodeficiency Diagnosis and Therapy, Shenzhen, China.
  • 3 Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Inserm UMR 1163, Paris, France.
  • 4 Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China.
  • 5 Shenzhen Engineering Laboratory of Primary Immunodeficiency Diagnosis and Therapy, Shenzhen, China.
  • 6 Department of Paediatrics, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
  • 7 Immunology and Pediatric Hematology Department, Necker Children's Hospital, AP-HP, Paris, France.
  • 8 Department of Paediatrics, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China; Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China; Shenzhen Engineering Laboratory of Primary Immunodeficiency Diagnosis and Therapy, Shenzhen, China. Electronic address: [email protected].
PMID: 29155103 DOI: 10.1016/j.jaci.2017.10.026
Abstract

Background: Autoimmune lymphoproliferative syndrome (ALPS) is a genetic disorder of lymphocyte homeostasis due to impaired Apoptosis. It was initially regarded as a very rare disease, but recent studies show that it may be more common than previously thought. Defects in a couple of genes have been identified in a proportion of patients with ALPS, but around one-third of such patients remain undefined genetically.

Objective: We describe 2 siblings presenting with ALPS-like disease. This study aimed to identify the genetic cause responsible for this phenotype.

Methods: Whole-exome sequencing and molecular and functional analyses were used to identify and characterize the genetic defect. Clinical and immunological analysis was also performed and reported.

Results: The 2 patients presented with chronic lymphadenopathy, hepatosplenomegaly, autoimmune hemolytic anemia, immune thrombocytopenia, and the presence of antinuclear autoantibody and other autoantibodies, but normal double-negative T cells. They also suffered from recurrent infections. Novel compound heterozygous mutations of RASGRP1 encoding Ras guanyl nucleotide releasing protein 1 were identified in the 2 siblings. The mutations impaired T-cell receptor signaling, leading to defective T-cell activation and proliferation, as well as impaired activation-induced cell death of T cells.

Conclusions: This study shows for the first time that RASGRP1 mutation should be considered in patients with ALPS-like disease. We also propose to investigate the intracellular proteins involved in the T-cell receptor signaling pathway in similar patients but with unknown genetic cause.

Keywords

ALPS-like disease; RasGRP1; T-cell receptor signaling; genetic defect; immune dysregulation; immunodeficiency.

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