Huawei Mao1, Wanling Yang2, Sylvain Latour3, Jing Yang2, Sarah Winter3, Jian Zheng4, Ke Ni4, Minmin Lv5, Chenjing Liu6, Hongmei Huang6, Koon-Wing Chan4, Pamela Pui-Wah Lee2, Wenwei Tu2, Alain Fischer7, Yu-Lung Lau8. 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: maohw@hku-szh.org. 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: lauylung@hku.hk.
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.
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.
Authors: Julio E Molineros; Bhupinder Singh; Chikashi Terao; Yukinori Okada; Jakub Kaplan; Barbara McDaniel; Shuji Akizuki; Celi Sun; Carol F Webb; Loren L Looger; Swapan K Nath Journal: Front Immunol Date: 2019-05-20 Impact factor: 7.561
Authors: Otavio Cabral-Marques; Lena F Schimke; Edgar Borges de Oliveira; Nadia El Khawanky; Rodrigo Nalio Ramos; Basel K Al-Ramadi; Gesmar Rodrigues Silva Segundo; Hans D Ochs; Antonio Condino-Neto Journal: Front Immunol Date: 2019-11-26 Impact factor: 7.561