Gene Expression Insights in Multiple Sclerosis: The Roles of IL7R, NFATc2, and RNF213 in Familial and Sporadic Cases

The article, "Expression and Clinical Significance of IL7R, NFATc2, and RNF213 in Familial and Sporadic Multiple Sclerosis" by Seyedeh Zahra Hosseini Imani et al., explores the differential expression of three key genes—IL7R, NFATc2, and RNF213—in multiple sclerosis (MS), a chronic autoimmune disease of the central nervous system (CNS). This study delves into how these genes, associated with inflammation and immune response, vary in expression between familial (hereditary) and sporadic (non-hereditary) MS cases and healthy controls.

Background and Rationale
Multiple sclerosis is characterized by myelin destruction and neuroinflammation, which are partly driven by cytokine release and immune dysregulation. Genetic predisposition is believed to play a role, with both HLA and non-HLA genes linked to MS susceptibility. The genes investigated in this study are known for their roles in immune regulation and inflammation. IL7R is involved in T-cell survival, NFATc2 plays a key role in the immune response through Wnt signaling, and RNF213 is implicated in inflammatory and angiogenic pathways. Given their relevance, studying their expression in familial and sporadic MS cases could enhance understanding of MS pathogenesis and reveal potential biomarkers.

Methodology
The researchers gathered blood samples from 72 MS patients (35 with sporadic MS and 37 with familial MS) and 74 healthy controls, some of whom were first-degree relatives (FDRs) of familial MS patients. Gene expression analysis was performed using quantitative real-time PCR, comparing the expression levels across four groups: sporadic MS patients, familial MS patients, FDRs, and unrelated healthy controls. Statistical analyses assessed the differences between groups, while receiver operating characteristic (ROC) curve analysis evaluated the diagnostic utility of these genes in predicting MS.

Key Findings
IL7R Expression: The study found significantly decreased IL7R expression in sporadic MS patients compared to familial patients, FDRs, and healthy controls. This suggests a link between IL7R downregulation and sporadic MS cases. Familial MS patients showed no significant difference in IL7R expression compared to their FDRs and healthy controls, indicating that IL7R downregulation may be specific to sporadic cases.

NFATc2 Expression: NFATc2 expression was upregulated in both sporadic and familial MS patients compared to healthy controls, suggesting an association with MS generally, regardless of hereditary background. This upregulation may reflect the gene's role in immune activation within MS pathogenesis. RNF213 Expression: RNF213 expression was significantly increased in familial MS patients relative to healthy controls, but there was no significant difference between sporadic MS patients and controls. This suggests that RNF213 expression changes might be more relevant in hereditary MS, possibly influenced by specific genetic variants within affected families.

Diagnostic Implications
The ROC analysis revealed that IL7R and NFATc2 could have diagnostic value, particularly in differentiating between MS patients and healthy individuals. The ROC curve for IL7R showed the highest diagnostic potential in distinguishing sporadic MS patients from healthy controls, with a high specificity and sensitivity. For NFATc2, the increased expression across MS cases points to its potential as a general diagnostic marker, though it does not differentiate between familial and sporadic cases effectively. The RNF213 gene, despite its association with familial MS, showed limited diagnostic utility.

Discussion and Future Directions
The differential expression patterns suggest that IL7R downregulation may be an early marker for sporadic MS, while NFATc2 upregulation could serve as a general indicator of MS-related inflammation. The role of RNF213 in familial MS cases, however, remains complex and requires further exploration to confirm its significance and underlying genetic drivers.

These findings highlight the need for larger studies to validate these gene expression changes across diverse populations and investigate their role as biomarkers for MS diagnosis and prognosis. Particularly, the use of IL7R and NFATc2 in clinical settings could aid in early MS detection and disease monitoring.

Conclusion
This study sheds light on the genetic underpinnings of MS, differentiating familial from sporadic cases through gene expression analysis of IL7R, NFATc2, and RNF213. The results emphasize IL7R's potential role as a sporadic MS biomarker and the need for targeted genetic testing in MS prognosis and diagnosis.

Reference:
Imani, S.Z.H., Hojati, Z., Khalilian, S. et al. Expression and clinical significance of IL7R, NFATc2, and RNF213 in familial and sporadic multiple sclerosis. Sci Rep 11, 19260 (2021).