The IGF-1 Deficit: How a Promoter Variation Compromises Myelin Repair in Multiple Sclerosis
Multiple Sclerosis (MS) is a complex and progressive immune-mediated disease where the immune system attacks myelin, the protective sheath covering nerves in the central nervous system (CNS). While the scientific community understands that the disease stems from a complicated interplay between genetics and the environment, the precise genetic triggers remain a subject of intense research. A compelling study by Shahbazi et al. (2017) offers a fresh perspective, proposing that a specific genetic mutation in the Insulin-like Growth Factor 1 (IGF-1) gene may be a key culprit in MS susceptibility.
The Critical Role of IGF-1 in the Nervous System
To understand the study's significance, we must first look at the biological function of IGF-1. While often recognized for its role in general growth, IGF-1 is arguably the most important growth factor for adults regarding nerve protection and anti-apoptosis (prevention of cell death). It plays a unique and vital role in the central nervous system as the only known survival factor for oligodendrocytes, the cells responsible for creating and maintaining myelin. Furthermore, IGF-1 protects neurons, stimulates astrocyte proliferation, and aids in the remyelination of damaged areas. Consequently, the researchers hypothesized that a genetic inability to produce sufficient IGF-1 could compromise the body's ability to repair the myelin damage caused by MS.
Investigating the Promoter Region
The research team conducted a case-control study involving an Iranian population, comprised of 339 MS patients and 431 healthy controls. Their primary goal was to analyze the promoter region of the IGF-1 gene—the section of DNA that initiates gene expression—to see if specific mutations correlated with the disease. Using techniques like Single-Strand Conformational Polymorphism (SSCP) and SSP-PCR, they screened for genetic variations and measured their functional impact on IGF-1 production levels in both blood plasma and cell cultures.
A Novel Genetic Link: The -383 C/T Polymorphism
The investigation yielded a significant discovery: a specific single nucleotide polymorphism (mutation) located at position -383 from the transcription start site. The data revealed a strong statistical association between this mutation and Multiple Sclerosis. Specifically, the presence of the C allele at this position was significantly more common in MS patients than in healthy individuals (p=0.001).
The genotypic distribution provided even deeper insight. The researchers found that individuals carrying the homozygous C/C genotype were far more likely to have MS compared to those with the standard T/T genotype (p < 0.001). To illustrate the disparity, the C / C genotype appeared in 9.4% of the MS patients, whereas it was present in only 4.2% of the healthy control group. This suggests that possessing the C/C genotype could significantly increase the odds of developing the disease compared to the T/T genotype.
Functional Consequences: Low IGF-1 Levels
The study went beyond identifying the mutation by determining its functional consequence. The researchers confirmed that MS patients generally had lower levels of IGF-1 mRNA compared to the control group (p=0.031). More importantly, they established a direct link between the specific genotype and protein production. Individuals with the high-risk C/C genotype produced significantly less IGF-1 in both in-vitro (cell culture) and in-vivo (blood serum) environments compared to those with the T/T genotype (p=0.004 and p=0.007, respectively).
Implications for Repair and Therapy
These findings suggest a mechanical explanation for the disease's progression in certain patients. The T/T genotype appears to be associated with high IGF-1 production, which is protective, while the C/C genotype leads to low expression. The authors propose that this low expression of IGF-1 contributes to a failure in the myelin recovery process within MS lesions. Because IGF-1 is essential for the differentiation of oligodendrocyte precursors and the synthesis of myelin, a genetic deficiency in this growth factor could leave the nervous system vulnerable to permanent damage.
While previous studies on IGF-1 levels in MS have produced conflicting results—with some showing no difference and others showing elevated levels—this study clarifies the picture by isolating a specific functional polymorphism. By linking the genetic code directly to protein production levels, Shahbazi et al. provide strong evidence that high IGF-1 production may play an important protective role. This insight opens the door for future therapeutic approaches that might focus on supplementing IGF-1 or boosting its expression to aid in neuroprotection and myelin repair for patients with this specific genetic profile.
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:
Shahbazi, M., Abdolmohammadi, R., Ebadi, H., & Farazmandfar, T. (2017). Novel functional polymorphism in IGF-1 gene associated with multiple sclerosis: a new insight to MS. Multiple sclerosis and related disorders, 13, 33-37.
