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

Furuyama, Hiroyasu; Chiba, Susumu; Okabayashi, Tamaki; Yokota, Shinichi; Nonaka, Michio; Imai, Tomihiro; Fujii, Nobuhiro; Matsumoto, Hiroyuki

doi:10.1016/j.jns.2006.06.012

Cited by 14 publications

(14 citation statements)

References 22 publications

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“…They are located in the promoter region, at positions -123 (C/A) and -88 (G/T), and affect the MxA expression level of [8][9][10]. A series of population-based studies have linked these SNPs to specific risks or clinical outcomes [11][12][13][14][15][16][17]. The flowering of such studies since the discovery of these first two SNPs highlights the crucial medical importance of MxA allelic variants as biomarkers of susceptibility or resistance to viral infections in humans.…”

Section: Introductionmentioning

confidence: 99%

Detection of new biallelic polymorphisms in the human MxA gene

et al. 2012

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The interferon-inducible human MxA protein plays an important role in innate defense against an array of viruses. One might expect allelic diversity at the MxA locus to influence the timing and magnitude of its expression or even the range of viruses whose biological cycle is inhibited by the encoded product. Here we have collected 267 samples of genomic DNA from three distinct populations (European, Asian, and African) and have systematically sequenced the promoter of the MxA gene and its 17 exons in order to inventory its allelic variants. Eighteen single-nucleotide polymorphisms were detected, four of which had never been identified before. Two of these, located in the promoter (at positions -309 and -101 respectively), might affect the MxA expression pattern. The other two result in substitutions (Gly255Glu and Val268Met) in the protein's N-terminal region that might directly affect its antiviral function.

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Section: Introductionmentioning

confidence: 99%

Detection of new biallelic polymorphisms in the human MxA gene

et al. 2012

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“…Expression of MxA was associated with −88 G/T SNP when PBMC cells were stimulated with IFN-α2 for 12 h (Fernandez-Arcas et al 2004). In one study (Furuyama et al 2006), the results of a luciferase reporter assay suggested that −123 SNP contributed to basal expression levels of MxA, whereas −88 SNP contributed to the induction of expression by IFNs. Ching et al (2010) further showed that the −123A allele had a stronger binding affinity to nuclear proteins from unstimulated cells and that the −88 T allele preferentially bound to the protein after IFN-β stimulation.…”

Section: Discussionmentioning

confidence: 99%

“…Around ISRE2, there are two single-nucleotide polymorphisms (SNPs) at nucleotide positions −88 and −123, which confer differences in the promoter activity and binding affinity to nuclear proteins (Hijikata et al 2001;Ching et al 2010). Promoter SNPs of MxA are reportedly associated with diseases, including hepatitis C (Hijikata et al 2000;Hijikata et al 2001), hepatitis B (Peng et al 2007), multiple sclerosis (Furuyama et al 2006), and subacute sclerosing panencephalitis (Torisu et al 2004). We previously reported the association of MxA promoter SNP with the severity of severe acute respiratory syndrome (SARS; Hamano et al 2005), and Ching et al (2010) reported its association with susceptibility to SARS in a larger case-control study.…”

Section: Introductionmentioning

confidence: 99%

MxA transcripts with distinct first exons and modulation of gene expression levels by single-nucleotide polymorphisms in human bronchial epithelial cells

et al. 2012

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Myxovirus resistance A (MxA) is a major interferon (IFN)-inducible antiviral protein. Promoter single-nucleotide polymorphisms (SNPs) of MxA near the IFN-stimulated response element (ISRE) have been frequently associated with various viral diseases, including emerging respiratory infections. We investigated the expression profile of MxA transcripts with distinct first exons in human bronchial epithelial cells. For primary culture, the bronchial epithelium was isolated from lung tissues with different genotypes, and total RNA was subjected to real-time reverse transcription polymerase chain reaction. The previously reported MxA transcript (T1) and a recently registered transcript with a distinct 5' first exon (T0) were identified. IFN-β and polyinosinic-polycytidylic acid induced approximately 100-fold higher expression of the T1 transcript than that of the T0 transcript, which also had a potential ISRE motif near its transcription start site. Even without inducers, the T1 transcript accounted for approximately two thirds of the total expression of MxA, levels of which were significantly associated with its promoter and exon 1 SNPs (rs17000900, rs2071430, and rs464138). Our results suggest that MxA observed in respiratory viral infections is possibly dominated by the T1 transcript and partly influenced by relevant 5' SNPs.

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“…It has previously been reported that a SNP at nucleotide position −88 (G or T) in the promoter region of the gene modulates MxA function at multiple levels including expression. MxA mRNA is significantly up-regulated with the mutant "T" (TT or GT) allele as compared to the wild type homozygous "G" allele (Fernandez-Arcas et al, 2004;Furuyama et al, 2006;Hijikata et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

The myxovirus resistance A (MxA) gene −88G>T single nucleotide polymorphism is associated with prostate cancer

Glymph

Mandal

Knowell

et al. 2013

Infection, Genetics and Evolution

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Background Myxovirus (influenza virus) resistance A (MxA) is an interferon stimulated antiviral protein that is required for a complete antiviral response. MxA polymorphism (rs2071430) is located within an Interferon Stimulated Response Element (ISRE) at position −88 in the gene’s promoter region, and it has been associated with increased susceptibility to infections and various diseases. In general, the low promoter activity genotype (GG) promotes susceptibility, whereas the high promoter activity genotype (TT) confers protection to Hepatitis C viral infection. MxA’s role in prostate cancer is not fully understood. Previous literature has shown that MxA may be a mediator of the effect of IFN on normal and tumor cell motility. MxA may act as a tumor suppressor and the level of expression may be a predictor of metastatic potential. Based on this information, in this study we investigated the association of this functional polymorphism (rs2071430) in MxA with prostate cancer. Methods Sample size and power was calculated using the PGA software. Genomic DNA from a controls (n=140) and prostate cancer patients (n=164) were used for genotyping SNP rs2071430 on all samples. Statistical analysis was performed using logistic regression model. Results A significant association was observed between rs2071430 genotype GG and prostate cancer. Individuals harboring the GG genotype are at an increased risk of prostate cancer. Data stratification reveals that the mutant GT genotype offers either offers some protection against prostate cancer in Caucasians. Conclusions MxA SNP rs2071430 GG genotype is significantly associated with prostate cancer irrespective of race. However, data stratification also suggests that the GT genotype is under-represented in Caucasian subjects suggesting its role in protection against prostate cancer in Caucasians. Although MxA is primarily implicated in viral infection, but it may be also be associated with prostate cancer. Recent studies have implicated viral and bacterial infections with increased prostate cancer risk. Expression of the high promoter activity genotype may offer resistance to prostate cancer infection and possibly influence clinical outcomes.

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

Cited by 14 publications

References 22 publications

Detection of new biallelic polymorphisms in the human MxA gene

Detection of new biallelic polymorphisms in the human MxA gene

MxA transcripts with distinct first exons and modulation of gene expression levels by single-nucleotide polymorphisms in human bronchial epithelial cells

The myxovirus resistance A (MxA) gene −88G>T single nucleotide polymorphism is associated with prostate cancer

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