Single nucleotide polymorphisms and functional analysis of MxA promoter region in multiple sclerosis
Hiroyasu Furuyama1, Susumu Chiba, Tamaki Okabayashi
1Department of Neurology, School of Medicine, Sapporo Medical University, Minami 1-jo Nishi 16-chome, Sapporo 060-8543, Japan. furuyama@sapmed.ac.jp
Objective:
Interferons (IFNs)-inducible myxovirus resistance protein A (MxA) has recently been used as an indirect marker of neutralizing antibody against IFN in patients with multiple sclerosis (MS). On the other hand, MxA inhibits the replication of viruses by means of modifying cellular function, including apoptotic pathway. Our objective is to investigate the genetic and pathological role of MxA in patients with MS.
Methods:
We examined SNPs of MxA promoter region in 67 patients with MS. Moreover, to elucidate the functional roles of SNPs, we conducted Luciferase assay with pGL3-basic vector including patient-derived or artificially mutated MxA promoter region.
Results:
A significantly higher frequency of the haplotype with -88T and -123A, which correlates with over-expression of MxA, was observed in MS. Moreover, we elucidated novel findings showing that nt -88 played a leading part with type I IFNs and that nt -123 played the same role independently without type I IFNs, respectively.
Conclusion:
SNPs on MxA promoter region may play an important role in the pathophysiology of MS and provide a novel strategy for the therapeutic resolutions of MS.
Insights
Genetic variations in the myxovirus resistance protein A (MxA) promoter region are linked to multiple sclerosis (MS) over-expression, suggesting a role in disease pathology and potential therapeutic strategies.
Area of Science:
- Immunogenetics
- Neuroimmunology
- Molecular Virology
Background:
- Myxovirus resistance protein A (MxA), an interferon-inducible protein, serves as an indirect marker for neutralizing antibodies against interferons in multiple sclerosis (MS).
- MxA possesses antiviral properties by modulating cellular functions, including the apoptotic pathway, which may be relevant to viral-mediated diseases like MS.
Purpose of the Study:
- To investigate the genetic and pathological significance of MxA in patients diagnosed with multiple sclerosis (MS).
- To explore the association between single nucleotide polymorphisms (SNPs) in the MxA promoter region and MS susceptibility or progression.
Main Methods:
- Genotyping of MxA promoter region single nucleotide polymorphisms (SNPs) was performed in a cohort of 67 MS patients.
- Functional analysis of identified SNPs was conducted using Luciferase assays with promoter constructs, including patient-derived and mutated variants.
Main Results:
- A significantly higher frequency of a specific haplotype (-88T and -123A) in the MxA promoter was observed in MS patients, correlating with MxA over-expression.
- Nucleotide -88 demonstrated a key role in MxA regulation in conjunction with type I interferons, while nucleotide -123 exhibited an independent regulatory role without type I interferons.
Conclusions:
- Single nucleotide polymorphisms (SNPs) within the MxA promoter region are implicated in the pathophysiology of multiple sclerosis (MS).
- These genetic findings offer a potential basis for novel therapeutic strategies targeting MxA pathways in MS management.
