Is DEXI a Multiple Sclerosis Susceptibility Gene? A Deep Dive

Multiple sclerosis (MS) is a complex autoimmune disorder with a strong genetic component. Recent research has expanded our understanding of the genes involved in MS, identifying over 200 genetic variants linked to the disease. One particularly interesting area of investigation is the 16p13 genomic region, which contains genes like CLEC16A , CIITA, SOCS1, and DEXI. A new review explores the potential role of dexamethasone-induced protein (DEXI) as a novel MS susceptibility gene.

The Genetic Landscape of MS
Genome-wide association studies (GWAS) have been instrumental in mapping the genetic landscape of MS. These studies have revealed that MS susceptibility is influenced by a complex interplay of genes involved in various processes within adaptive and innate immune cells, as well as brain-resident microglia.

* Early studies highlighted the importance of genes associated with the immune system, particularly T cells, in MS development.

* More recent GWAS have identified a variant in the DYSF-ZNF638 locus associated with MS progression, suggesting different mechanisms drive disease onset and progression.

* The C-type lectin domain family 16, member A (CLEC16A ) gene within the 16p13 region has been consistently linked to increased risk of MS and other autoimmune disorders.

The 16p13 Region and DEXI
The CLEC16A gene has been a prime focus due to its strong association with MS susceptibility. However, MS-associated single nucleotide polymorphisms (SNPs) within CLEC16A are primarily located in introns, suggesting they may regulate the expression of nearby genes in addition to CLEC16A . This is where DEXI comes into play.

The DEXI gene, located between CLEC16A and CIITA in the 16p13 region, has garnered attention because MS-associated CLEC16A SNPs act as cis-expression quantitative trait loci (eQTLs) for DEXI, meaning these SNPs influence DEXI expression. Specifically, studies have shown that SNPs in linkage disequilibrium (LD) with CLEC16A SNPs also function as eQTLs for DEXI in various immune cells and brain tissue.

DEXI and Autoimmunity
Genetic variants in CLEC16A have been linked to multiple autoimmune disorders, suggesting a broad role in autoimmunity. Interestingly, studies have identified both MS and type-1 diabetes (T1D)-associated CLEC16A SNPs as eQTLs for DEXI. The risk alleles of these SNPs correlate with lower DEXI expression, implying that DEXI may have a broader role in the pathogenesis of autoimmunity.

Further analysis using the Genotype-Tissue Expression Portal revealed that MS-associated SNPs act as eQTLs for DEXI in various tissues beyond the brain and peripheral blood, indicating a potential regulatory function independent of cell type. Chromatin conformation capture assays have also shown that intronic CLEC16A sequences are in physical proximity to the DEXI promoter, suggesting that these regions may contain regulatory elements that influence DEXI expression levels.

DEXI Expression and Function
DEXI is a ubiquitously expressed gene, with higher expression in the lungs, kidney, and spleen. Notably, DEXI expression is highest in Epstein–Barr virus (EBV)-transformed B lymphocytes.

While initially identified as a dexamethasone-induced transcript, subsequent studies have not consistently replicated this finding. However, DEXI expression is increased in pancreatic beta cells upon induction of inflammation and apoptosis and as monocytes differentiate into macrophages. Interestingly, DEXI expression is downmodulated in T cells upon activation, with a more pronounced effect observed in CD4+ T cells from MS patients compared to healthy controls. Despite the downmodulation of DEXI mRNA expression upon T cell activation, the nuclear presence of the DEXI protein increases. This suggests a potential role for DEXI in regulating gene expression within the nucleus.

Functional Studies and Future Directions
Functional assessments of DEXI in relation to autoimmune disorders are still limited. Studies in nonobese diabetic (NOD) mice have yielded conflicting results regarding the role of DEXI in T1D. Some studies suggest that CLEC16A , rather than DEXI, is the causal gene for the T1D associations in the 16p13 gene region. Although overexpression of DEXI did not affect T cell activation in vitro, the increased nuclear presence of DEXI protein upon T cell activation suggests a potential role in nuclear processes such as gene expression regulation.

Future studies are needed to clarify the function of DEXI in MS and other autoimmune diseases:

* Investigating the role of DEXI in EBV infection, given its high expression in EBV-transformed lymphocytes.
* Exploring the potential cell-specific roles of DEXI in different immune cell types.
* Conducting functional genomic screens to identify genes and pathways that interact with or are regulated by DEXI.
* Utilizing animal models, such as experimental autoimmune encephalomyelitis (EAE) in DEXI knockout mice, to gain insights into the role of DEXI in MS disease processes.
* Incorporating microglia into future expression and functional studies, as these brain-resident immune cells may contribute to the eQTL signals observed in brain tissue.

Conclusion
DEXI has emerged as a potential MS susceptibility gene based on eQTL analyses. Intronic CLEC16A susceptibility SNPs correlate with reduced DEXI expression across various cells and tissues, and DEXI expression is affected by external stimuli in different cells. While the precise role of DEXI in MS remains to be determined, its involvement in immune cell function and gene expression regulation warrants further investigation. Understanding DEXI and its complex networks may reveal new biological pathways relevant to MS and other autoimmune disorders, potentially guiding the development of novel treatment interventions.

Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

References:
Eriksson, A. M., Emini, N., Harbo, H. F., & Berge, T. (2025). Is DEXI a Multiple Sclerosis Susceptibility Gene?. International Journal of Molecular Sciences, 26(3), 1175.