An SNP in the trinucleotide repeat region of the TNRC6A gene maps to a major TNGW1 autoepitope in patients with autoantibodies to GW182.

GW/P bodies contain two TNRC6A protein isoforms (GW182 and TNGW1) that function as translational repressors of mRNA through Ago2-mediated RNA silencing. Autoantibodies to GW/P body components GW182, Ge-1 and Ago2 have previously been correlated with clinical autoimmune diseases including neurological disease, Sjögren's syndrome, systemic lupus erythematosus, rheumatoid arthritis and primary biliary cirrhosis. No studies were published to date examining if patients with autoantibodies directed against GW/P bodies contain autoantibodies to the trinucleotide repeat (TNR) region of TNGW1, which differs from GW182 only by the addition of an N-terminal QP-rich 253 amino acid sequence. Our data show that 85.7% of GW/P body positive plasma contain autoantibodies to various epitopes in the TNR region of TNGW1. Given the association of neurological diseases with autoantibodies directed to the TNR region on exon 5 of TNRC6A, this study examined whether there were TNR expansions as described in other neurological diseases and/or mutations in the nucleotide sequence of the CAG/CCA/G-rich region in seven anti-GW/P body positive patients, six control and eight breast cancer patients. Although a TNR expansion was not identified, 28.6% of patients containing autoantibodies to the TNR of TNGW1 were shown to have a single nucleotide polymorphism (SNP) at c.344C > A in the CAG/CCA/G-rich region of TNRC6A, which when translated, would produce a protein variant of p.Pro115Gln. The amino acid change may alter the structure of TNGW1 and/or perturb its miRNA regulatory function although this has not been examined experimentally. A putative change in protein structure may lead to a loss of tolerance to the TNGW1 protein or result in a "neo-antigen" in patients containing the specific TNRC6A SNPs. Further studies of a larger cohort of GW/P body positive patients and structure-function relationships of the variant TNRC6A are required to fully understand the role that such SNPs play in GW/P body autoantibody production and/or pathogenesis of related autoimmune diseases.