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 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. In Nov 15, 2017, Huawei Mao and others published an article in << Journal of Allergy and Clinical Immunology >> which title is “RASGRP1 mutation in autoimmune lymphoproliferative syndrome-like disease”.
They described two siblings presenting with ALPS-like disease. This study aimed to identify the genetic cause responsible for this phenotype. The 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.
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 TCR signaling pathway in similar patients but with unknown genetic cause.
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