Single nucleotide polymorphisms and functional analysis of MxA promoter region in multiple sclerosis.
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.


CONCLUSIONS
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.
Furuyama
Hiroyasu
H
Department of Neurology, School of Medicine, Sapporo Medical University, Minami 1-jo Nishi 16-chome, Sapporo 060-8543, Japan. furuyama@sapmed.ac.jp
Chiba
Susumu
S
Okabayashi
Tamaki
T
Yokota
Shin-ichi
S
Nonaka
Michio
M
Imai
Tomihiro
T
Fujii
Nobuhiro
N
Matsumoto
Hiroyuki
H
D000328:Adult; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D019204:GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D005786:Gene Expression Regulation; D005787:Gene Frequency; D017930:Genes, Reporter; D006239:Haplotypes / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007370:Interferon Type I / Q000502:physiology; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics*; D064547:Myxovirus Resistance Proteins; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000032:analysis / Q000096:biosynthesis
D007370:Interferon Type I; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D011993:Recombinant Fusion Proteins; D008156:Luciferases; D019204:GTP-Binding Proteins