Is DEXI a Multiple Sclerosis Susceptibility Gene?

The genetic landscape of multiple sclerosis (MS) has been extensively mapped, yielding significant insights into the molecular mechanisms of the disorder. Early studies highlighted key genes associated with the immune system, particularly T cells, as critical for MS susceptibility. Subsequent large-scale genome-wide association studies (GWASs) identified over 200 genetic variants linked to MS, revealing a complex interplay between MS risk and genes involved in various processes within adaptive and innate immune cells, as well as brain-resident microglia. Recently, a groundbreaking GWAS pinpointed the first gene variant associated with MS disease progression, distinguishing the mechanisms driving disease onset from those influencing progression. The C-type lectin domain family 16, member A (CLEC16A) gene within the 16p13 region has consistently been shown to be associated with increased risk of developing both MS and other autoimmune disorders. Notably, several autoimmune-associated genetic variants in CLEC16A introns act as expression quantitative trait loci for the dexamethasone-induced protein (DEXI gene, adding DEXI to the growing list of MS susceptibility genes. This review explores the molecular and functional characterization of DEXI with a particular focus on recent advances in understanding its role in autoimmunity, specifically in the context of multiple sclerosis. We underscore the importance of continued molecular investigation of susceptibility loci for MS identified in genetic studies, with the goal of translating this knowledge into clinical applications.