{Reference Type}: Case Reports
{Title}: RASGRP1 mutation in autoimmune lymphoproliferative syndrome-like disease.
{Author}: Mao H;Yang W;Latour S;Yang J;Winter S;Zheng J;Ni K;Lv M;Liu C;Huang H;Chan KW;Pui-Wah Lee P;Tu W;Fischer A;Lau YL;
{Journal}: J Allergy Clin Immunol
{Volume}: 142
{Issue}: 2
{Year}: 08 2018
{Factor}: 14.29
{DOI}: 10.1016/j.jaci.2017.10.026
{Abstract}: 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.<BR>We describe 2 siblings presenting with ALPS-like disease. This study aimed to identify the genetic cause responsible for this phenotype.<BR>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.<BR>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.<BR>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.