RASGRP1mutation in autoimmune lymphoproliferative syndrome-like disease

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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 ofRASGRP1encoding 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 thatRASGRP1mutation 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.

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