RASGRP1 mutation in autoimmune lymphoproliferative syndrome-like disease - 04/08/18
, Wanling Yang, PhD b, c, Sylvain Latour, PhD d, Jing Yang, PhD b, c, Sarah Winter, PhD d, Jian Zheng, PhD b, Ke Ni, MPhil b, Minmin Lv, MPhil c, Chenjing Liu, MPhil a, Hongmei Huang, MD a, Koon-Wing Chan, MPhil b, Pamela Pui-Wah Lee, MD b, c, Wenwei Tu, PhD b, c, Alain Fischer, MD, PhD e, Yu-Lung Lau, MD a, b, c, ⁎ 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.
Le texte complet de cet article est disponible en PDF.Key words : ALPS-like disease, RasGRP1, immunodeficiency, immune dysregulation, T-cell receptor signaling, genetic defect
Abbreviations used : ALPS, ANA, DAG, DNT, ERK, RasGRP1, TCR, SLE
Plan
| This study was supported partly by grants from the National Natural Science Foundation of China (grant no. 81671626 to H.M.), Shenzhen Science, Technology and Innovation Commission (grant no. JCYJ20140411175241066 to H.M.), the Shenzhen Development and Reform Commission (grant no. [2015]164 to Y.-L.L. and H. M.), Hong Kong Health and Medical Research Fund (grant no. 01120846 to W.Y., Y.-L.L., and P.P.-W.L.), and the Society for the Relief of Disabled Children (to Y.-L.L.). |
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| Disclosure of potential conflict of interest: S. Latour is employed by CNRS, France. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 142 - N° 2
P. 595 - août 2018 Retour au numéro
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