Exploring Gene Expression Profiles in Multiple Sclerosis: Key Insights from YAP1, TAZ, CRB3, and VDR in Familial and Sporadic MS

Multiple Sclerosis (MS) is a complex immune-mediated neurodegenerative disease affecting the central nervous system (CNS), leading to demyelination and nerve damage. The study, titled "Gene expression profiles of YAP1, TAZ, CRB3, and VDR in familial and sporadic multiple sclerosis among an Iranian population," provides insight into the differential expression of genes YAP1, TAZ, CRB3, and VDR, all implicated in myelination and immune regulation in MS. Conducted on a sample from Iran, this study evaluates the expression profiles across familial and sporadic MS cases and compares them to healthy individuals, including first-degree relatives of familial MS patients. By distinguishing the expression patterns, this study offers valuable information on potential biomarkers and targets for personalized MS treatment.

The Hippo Pathway and VDR in Myelination
The Hippo signaling pathway, critical for cell proliferation and organ size regulation, involves YAP1 and TAZ as key effectors. These genes regulate transcription and are essential for the myelination of nerve fibers. CRB3, an inhibitor of the Hippo pathway, further controls the expression of YAP1 and TAZ, suggesting a feedback mechanism in the nervous system. Additionally, Vitamin D receptor (VDR), influenced by TAZ, has neuroprotective roles through its active form, 1,25-dihydroxyvitamin D, which crosses the blood-brain barrier and promotes oligodendrocyte differentiation. The study highlights these pathways as critical regulators in MS pathogenesis, especially as variations in their expression could indicate familial or sporadic MS susceptibility.

Methods
The study included 35 sporadic MS patients, 37 familial MS patients, 34 healthy first-degree relatives (HFR), and 40 healthy controls. Blood samples were collected, and total RNA was extracted for cDNA synthesis and quantitative PCR. Gene expression levels were normalized using ACTB as a reference gene. Statistical analysis identified significant differences in gene expression across groups, using one-way ANOVA and ROC curves to assess diagnostic potential.

Results
VDR Expression: The VDR gene expression was notably higher in sporadic MS patients compared to familial MS patients, HFRs, and healthy controls. This increase suggests VDR’s significant role in sporadic MS, potentially related to differences in vitamin D metabolism and its neuroprotective functions.

TAZ Expression: The TAZ expression was elevated in both familial MS patients and HFRs when compared to controls, implying that TAZ may serve as a predisposing factor in familial MS cases. This trend also supports the hypothesis that familial aggregation may involve genetic regulation that predisposes relatives to the disease.

YAP1 and CRB3 Expression: Both YAP1 and CRB3 exhibited contrasting expressions, with decreased YAP1 and increased CRB3 in MS patients relative to controls. The suppression of YAP1 by CRB3 in the Hippo pathway aligns with the demyelination seen in MS, suggesting that these alterations disrupt myelination processes. Notably, HFRs showed elevated YAP1, indicating a potential resilience or delayed onset in asymptomatic relatives.

Diagnostic Potential and Clinical Associations
The study performed ROC curve analyses to evaluate these genes as biomarkers. VDR and CRB3 demonstrated significant AUC values, indicating their diagnostic potential in distinguishing MS forms. Furthermore, a correlation was found between VDR expression and the Expanded Disability Status Scale (EDSS) in familial patients, suggesting that VDR could reflect disease severity in familial MS. Although the sample size limits broader generalizations, these findings hint at the relevance of gene expression profiles in clinical assessment and risk prediction.

Discussion and Future Directions
The study opens avenues for investigating the Hippo pathway and VDR as therapeutic targets, as modulating these pathways might support remyelination and reduce MS progression. The differential expression in familial versus sporadic MS cases suggests that personalized treatment approaches could benefit from genetic profiling. Future studies with larger cohorts could refine these insights and expand on the impact of genetic variations, such as SNPs, on gene expression in MS. Examining additional genes in the Hippo pathway, including MST and LATS, could further clarify the roles of YAP1, TAZ, and CRB3.

Conclusion
This study underscores the complexity of MS and the value of genetic insights for understanding its pathology. VDR, TAZ, YAP1, and CRB3 gene expressions reveal potential biomarkers that could aid in differentiating familial from sporadic MS. By advancing biomarker research, this work contributes to the evolving landscape of personalized MS treatments, aiming for more targeted and effective therapeutic strategies based on genetic predispositions.

Reference:
Khalilian, S., Hojati, Z., Dehghanian, F. et al. Gene expression profiles of YAP1, TAZ, CRB3, and VDR in familial and sporadic multiple sclerosis among an Iranian population. Sci Rep 11, 7713 (2021).