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.
- 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].
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.