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Functional analysis of RasGRP1 SNPs in autoimmune disease

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Single nucleotide polymorphisms in autoimmunity-associated genes

Autoimmunity is a chronic inflammatory condition mediated by T and B lymphocytes. Current treatments fail to cure the disease, necessitating alternative targeted solutions.

Fundamental Research
Health

Development of autoimmunity involves impairment of the mechanisms of lymphocyte selection. This leads to production of autoantibodies that can trigger immune responses to various tissues and organs. Several types of immune cells and biological processes have been implicated in autoimmunity, including the aberrant stimulation of B cells by CD4+ T cells. Genome-wide association studies on the autoimmune disease systemic lupus erythematosus (SLE) have unveiled susceptibility genes, increasing our understanding of the genetic basis of the disease. However, little is known about the deregulated signalling pathways in T or B cells of SLE patients. In addition, single nucleotide polymorphisms (SNPs) near the RasGRP1 gene have been associated with susceptibility to autoimmune disease, while RasGRP1 splice variants have been identified in SLE patients. RasGRP1 is an important guanine nucleotide exchange factor that acts downstream of the T cell antigen receptor. Furthermore, microRNA-driven downregulation of RasGRP1 expression has been postulated to play a role in CD4+ T cell function through an unknown mechanism. The EU-funded AUTOIMMUNITY RASGRP1 project investigated how SNPs and mutations in RasGRP1 are involved in the development of autoimmune diseases. Scientists established a cell line-based system and screened the effect of point-mutations on RasGRP1 function and downstream signalling. The team discovered that several SNPs impacted RasGRP1 activity while structural insight was obtained regarding the conversion of the protein from an inactive to an active state. They also detected aberrant RasGRP1 expression levels in samples from patients with active disease that can be regulated by the RasGRP1 enhancer regions. Overall, the results of the AUTOIMMUNITY RASGRP1 project provided fundamental knowledge on how RasGRP1 activity and expression are regulated. The structure to function studies will help towards the future development of small molecule inhibitors to down-regulate the aberrant RasGRP1 expression seen in autoimmune diseases. Given the implication of RasGRP1 in cancer, the clinical relevance of these findings extends beyond autoimmunity.

Keywords

Single nucleotide polymorphisms, autoimmunity, systemic lupus erythematosus, RasGRP1, AUTOIMMUNITY RASGRP1

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