RASGRP1 mutation in autoimmune lymphoproliferative syndrome-like disease

Publication date: Available online 15 November 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Huawei Mao, Wanling Yang, Sylvain Latour, Jing Yang, Sarah Winter, Jian Zheng, Ke Ni, Minmin Lv, Chenjing Liu, Hongmei Huang, Koon-Wing Chan, Pamela Pui-Wah Lee, Wenwei Tu, Alain Fischer, Yu-Lung Lau
BackgroundAutoimmune 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 it may be more common than previously thought. Defects in a couple of genes have been identified in a proportion of ALPS patients, but around one third of such patients remain undefined genetically.ObjectiveWe described two siblings presenting with ALPS-like disease. This study aimed to identify the genetic cause responsible for this phenotype.MethodsWhole exome sequencing, molecular and functional analyses were used to identify and characterize the genetic defect. Clinical and immunological analysis was also performed and reported.ResultsThe two patients presented with chronic lymphadenopathy, hepatosplenomegaly, autoimmune hemolytic anemia, immune thrombocytopenia, presence of ANA 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 two siblings. The mutations impaired TCR signaling, leading to defective T cell activation and proliferation, as well as impaired activation-induced cell death of T cells.ConclusionThis 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 TCR signaling pathway in similar patients but with unknown genetic cause.

Teaser

Capsule Summary:ALPS can arise from a number of different genetic causes. Here, we show for the first time that RASGRP1 mutations are involved in ALPS-like disease, and highlight the critical role of RasGRP1 in maintaining tolerance and homeostasis.


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