Abnormalities in alternative splicing (AS) are emerging as recurrent features in
autoimmune diseases (
AIDs). In particular, a growing body of evidence suggests the existence of a pathogenic association between a generalized defect in splicing regulatory genes and
multiple sclerosis (MS). Moreover, several studies have documented an unbalance in alternatively-spliced
isoforms in MS patients possibly contributing to the disease etiology. In this work, using a combination of PCR-based techniques (reverse-transcription (RT)-PCR, fluorescent-competitive, real-time, and digital RT-PCR assays), we investigated the alternatively-
spliced gene encoding Gasdermin B, GSDMB, which was repeatedly associated with susceptibility to
asthma and
AIDs. The in-depth characterization of GSDMB AS and backsplicing profiles led us to the identification of an exonic
circular RNA (ecircRNA) as well as of novel GSDMB in-frame and out-of-frame
isoforms. The non-productive splicing variants were shown to be downregulated by the nonsense-mediated mRNA decay (NMD) in human cell lines, suggesting that GSDMB levels are significantly modulated by NMD. Importantly, both AS
isoforms and the identified ecircRNA were significantly dysregulated in peripheral blood mononuclear cells of relapsing-remitting MS patients compared to controls, further supporting the notion that aberrant
RNA metabolism is a characteristic feature of the disease.