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Article: Variation in antiviral 2′,5′-oligoadenylate synthetase (2′5′AS) enzyme activity is controlled by a single-nucleotide polymorphism at a splice-acceptor site in the OAS1 gene

TitleVariation in antiviral 2′,5′-oligoadenylate synthetase (2′5′AS) enzyme activity is controlled by a single-nucleotide polymorphism at a splice-acceptor site in the OAS1 gene
Authors
Issue Date2005
PublisherCell Press. The Journal's web site is located at http://www.cell.com/AJHG/
Citation
American Journal Of Human Genetics, 2005, v. 76 n. 4, p. 623-633 How to Cite?
AbstractIt is likely that human genetic differences mediate susceptibility to viral infection and virus-triggered disorders. OAS genes encoding the antiviral enzyme 2′,5′-oligoadenylate synthetase (2′5′AS) are critical components of the innate immune response to viruses. This enzyme uses adenosine triphosphate in 2′-specific nucleotidyl transfer reactions to synthesize 2′,5′-oligoadenylates, which activate latent ribonuclease, resulting in degradation of viral RNA and inhibition of virus replication. We showed elsewhere that constitutive (basal) activity of 2′5′AS is correlated with virus-stimulated activity. In the present study, we asked whether constitutive activity is genetically determined and, if so, by which variants. Analysis of 83 families containing two parents and two children demonstrated significant correlations between basal activity in parent-child pairs (P < .0001) and sibling pairs (P = .0044), but not spousal pairs, suggesting strong genetic control of basal activity. We next analyzed association between basal activity and 15 markers across the OAS gene cluster. Significant association was detected at multiple markers, the strongest being at an A/G single-nucleotide polymorphism at the exon 7 splice-acceptor site (AG or AA) of the OAS1 gene. At this unusual polymorphism, allele G had a higher gene frequency in persons with high enzyme activity than in those with low enzyme activity (0.44 vs. 0.20; P = 3 × 10 -14). Enzyme activity varied in a dose-dependent manner across the GG, GA, and AA genotypes (tested by analysis of variance; P = 1 × 10 -14). Allele G generates the previously described p46 enzyme isoform, whereas allele A ablates the splice site and generates a dual-function antiviral/proapoptotic p48 isoform and a novel p52 isoform. This genetic polymorphism makes OAS1 an excellent candidate for a human gene that influences host susceptibility to viral infection. © 2005 by The American Society of Human Genetics. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/43149
ISSN
2015 Impact Factor: 10.794
2015 SCImago Journal Rankings: 8.769
PubMed Central ID
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorBonnevieNielsen, Ven_HK
dc.contributor.authorField, LLen_HK
dc.contributor.authorLu, Sen_HK
dc.contributor.authorZheng, DJen_HK
dc.contributor.authorLi, Men_HK
dc.contributor.authorMartensen, PMen_HK
dc.contributor.authorNielsen, TBen_HK
dc.contributor.authorBeckNielsen, Hen_HK
dc.contributor.authorLau, YLen_HK
dc.contributor.authorPociot, Fen_HK
dc.date.accessioned2007-03-23T04:40:01Z-
dc.date.available2007-03-23T04:40:01Z-
dc.date.issued2005en_HK
dc.identifier.citationAmerican Journal Of Human Genetics, 2005, v. 76 n. 4, p. 623-633en_HK
dc.identifier.issn0002-9297en_HK
dc.identifier.urihttp://hdl.handle.net/10722/43149-
dc.description.abstractIt is likely that human genetic differences mediate susceptibility to viral infection and virus-triggered disorders. OAS genes encoding the antiviral enzyme 2′,5′-oligoadenylate synthetase (2′5′AS) are critical components of the innate immune response to viruses. This enzyme uses adenosine triphosphate in 2′-specific nucleotidyl transfer reactions to synthesize 2′,5′-oligoadenylates, which activate latent ribonuclease, resulting in degradation of viral RNA and inhibition of virus replication. We showed elsewhere that constitutive (basal) activity of 2′5′AS is correlated with virus-stimulated activity. In the present study, we asked whether constitutive activity is genetically determined and, if so, by which variants. Analysis of 83 families containing two parents and two children demonstrated significant correlations between basal activity in parent-child pairs (P < .0001) and sibling pairs (P = .0044), but not spousal pairs, suggesting strong genetic control of basal activity. We next analyzed association between basal activity and 15 markers across the OAS gene cluster. Significant association was detected at multiple markers, the strongest being at an A/G single-nucleotide polymorphism at the exon 7 splice-acceptor site (AG or AA) of the OAS1 gene. At this unusual polymorphism, allele G had a higher gene frequency in persons with high enzyme activity than in those with low enzyme activity (0.44 vs. 0.20; P = 3 × 10 -14). Enzyme activity varied in a dose-dependent manner across the GG, GA, and AA genotypes (tested by analysis of variance; P = 1 × 10 -14). Allele G generates the previously described p46 enzyme isoform, whereas allele A ablates the splice site and generates a dual-function antiviral/proapoptotic p48 isoform and a novel p52 isoform. This genetic polymorphism makes OAS1 an excellent candidate for a human gene that influences host susceptibility to viral infection. © 2005 by The American Society of Human Genetics. All rights reserved.en_HK
dc.format.extent357370 bytes-
dc.format.extent3258 bytes-
dc.format.mimetypeapplication/pdf-
dc.format.mimetypetext/plain-
dc.languageengen_HK
dc.publisherCell Press. The Journal's web site is located at http://www.cell.com/AJHG/en_HK
dc.relation.ispartofAmerican Journal of Human Geneticsen_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.rightsAmerican Journal of Human Genetics. Copyright © University of Chicago Press.en_HK
dc.subject.meshAmino acid sequenceen_HK
dc.subject.meshBase sequenceen_HK
dc.subject.meshMolecular sequence dataen_HK
dc.subject.meshPolymorphism, single nucleotideen_HK
dc.subject.meshRna splice sites - geneticsen_HK
dc.titleVariation in antiviral 2′,5′-oligoadenylate synthetase (2′5′AS) enzyme activity is controlled by a single-nucleotide polymorphism at a splice-acceptor site in the OAS1 geneen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0002-9297&volume=76&spage=623&epage=633&date=2005&atitle=Variation+in+Antiviral+2%27,5%27-Oligoadenylate+Synthetase+(2%275%27AS)+Enzyme+Activity+Is+Controlled+by+a+Single-Nucleotide+Polymorphism+at+a+Splice-Acceptor+Site+in+the+OAS1+Geneen_HK
dc.identifier.emailLau, YL:lauylung@hkucc.hku.hken_HK
dc.identifier.authorityLau, YL=rp00361en_HK
dc.description.naturepublished_or_final_versionen_HK
dc.identifier.doi10.1086/429391en_HK
dc.identifier.pmid15732009en_HK
dc.identifier.pmcidPMC1199299-
dc.identifier.scopuseid_2-s2.0-20144389631en_HK
dc.identifier.hkuros97631-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-20144389631&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume76en_HK
dc.identifier.issue4en_HK
dc.identifier.spage623en_HK
dc.identifier.epage633en_HK
dc.identifier.isiWOS:000227516000008-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridBonnevieNielsen, V=7004218076en_HK
dc.identifier.scopusauthoridField, LL=35599995600en_HK
dc.identifier.scopusauthoridLu, S=8854473600en_HK
dc.identifier.scopusauthoridZheng, DJ=8209867700en_HK
dc.identifier.scopusauthoridLi, M=16025211400en_HK
dc.identifier.scopusauthoridMartensen, PM=6603556668en_HK
dc.identifier.scopusauthoridNielsen, TB=7201759470en_HK
dc.identifier.scopusauthoridBeckNielsen, H=7102424554en_HK
dc.identifier.scopusauthoridLau, YL=7201403380en_HK
dc.identifier.scopusauthoridPociot, F=7005502287en_HK

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