A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis

Handle URI:
http://hdl.handle.net/10754/325258
Title:
A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis
Authors:
Heckmann, J M; Uwimpuhwe, H; Ballo, R; Kaur, M; Bajic, Vladimir B. ( 0000-0001-5435-4750 ) ; Prince, S
Abstract:
Complement activation in myasthenia gravis (MG) may damage muscle endplate and complement regulatory proteins such as decay-accelerating factor (DAF) or CD55 may be protective. We hypothesize that the increased prevalence of severe extraocular muscle (EOM) dysfunction among African MG subjects reported earlier may result from altered DAF expression. To test this hypothesis, we screened the DAF gene sequences relevant to the classical complement pathway and found an association between myasthenics with EOM paresis and the DAF regulatory region c.-198CG SNP (odds ratio8.6; P0.0003). This single nucleotide polymorphism (SNP) results in a twofold activation of a DAF 5?-flanking region luciferase reporter transfected into three different cell lines. Direct matching of the surrounding SNP sequence within the DAF regulatory region with the known transcription factor-binding sites suggests a loss of an Sp1-binding site. This was supported by the observation that the c.-198CG SNP did not show the normal lipopolysaccharide-induced DAF transcriptional upregulation in lymphoblasts from four patients. Our findings suggest that at critical periods during autoimmune MG, this SNP may result in inadequate DAF upregulation with consequent complement-mediated EOM damage. Susceptible individuals may benefit from anti-complement therapy in addition to immunosuppression. © 2010 Macmillan Publishers Limited. All rights reserved.
KAUST Department:
Computational Bioscience Research Center (CBRC)
Citation:
Heckmann JM, Uwimpuhwe H, Ballo R, Kaur M, Bajic VB, et al. (2010) A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis. Genes and Immunity 11: 1-10. doi:10.1038/gene.2009.61.
Publisher:
Springer Nature
Journal:
Genes and Immunity
Issue Date:
13-Aug-2009
DOI:
10.1038/gene.2009.61
PubMed ID:
19675582
PubMed Central ID:
PMC2834500
Type:
Article
ISSN:
14664879
Appears in Collections:
Articles; Computational Bioscience Research Center (CBRC)

Full metadata record

DC FieldValue Language
dc.contributor.authorHeckmann, J Men
dc.contributor.authorUwimpuhwe, Hen
dc.contributor.authorBallo, Ren
dc.contributor.authorKaur, Men
dc.contributor.authorBajic, Vladimir B.en
dc.contributor.authorPrince, Sen
dc.date.accessioned2014-08-27T09:42:57Z-
dc.date.available2014-08-27T09:42:57Z-
dc.date.issued2009-08-13en
dc.identifier.citationHeckmann JM, Uwimpuhwe H, Ballo R, Kaur M, Bajic VB, et al. (2010) A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis. Genes and Immunity 11: 1-10. doi:10.1038/gene.2009.61.en
dc.identifier.issn14664879en
dc.identifier.pmid19675582en
dc.identifier.doi10.1038/gene.2009.61en
dc.identifier.urihttp://hdl.handle.net/10754/325258en
dc.description.abstractComplement activation in myasthenia gravis (MG) may damage muscle endplate and complement regulatory proteins such as decay-accelerating factor (DAF) or CD55 may be protective. We hypothesize that the increased prevalence of severe extraocular muscle (EOM) dysfunction among African MG subjects reported earlier may result from altered DAF expression. To test this hypothesis, we screened the DAF gene sequences relevant to the classical complement pathway and found an association between myasthenics with EOM paresis and the DAF regulatory region c.-198CG SNP (odds ratio8.6; P0.0003). This single nucleotide polymorphism (SNP) results in a twofold activation of a DAF 5?-flanking region luciferase reporter transfected into three different cell lines. Direct matching of the surrounding SNP sequence within the DAF regulatory region with the known transcription factor-binding sites suggests a loss of an Sp1-binding site. This was supported by the observation that the c.-198CG SNP did not show the normal lipopolysaccharide-induced DAF transcriptional upregulation in lymphoblasts from four patients. Our findings suggest that at critical periods during autoimmune MG, this SNP may result in inadequate DAF upregulation with consequent complement-mediated EOM damage. Susceptible individuals may benefit from anti-complement therapy in addition to immunosuppression. © 2010 Macmillan Publishers Limited. All rights reserved.en
dc.language.isoenen
dc.publisherSpringer Natureen
dc.rightsThis work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Licence. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectCD55en
dc.subjectComplementen
dc.subjectDecay-accelerating factoren
dc.subjectExtraocular musclesen
dc.subjectMyasthenia gravisen
dc.subjectRegulatory single nucleotide polymorphismen
dc.subjectdecay accelerating factoren
dc.subjectluciferaseen
dc.subjecttranscription factor Sp1en
dc.subjectanimal cellen
dc.subjectbinding siteen
dc.subjectcancer cell cultureen
dc.subjectcell strain COS7en
dc.subjectcomplement classical pathwayen
dc.subjectcontrolled studyen
dc.subjectdisease severityen
dc.subjectDNA flanking regionen
dc.subjectgenetic associationen
dc.subjectgenetic transfectionen
dc.subjecthigh risk patienten
dc.subjecthuman cellen
dc.subjectimmunosuppressive treatmenten
dc.subjectlymphoblasten
dc.subjectmajor clinical studyen
dc.subjectmouseen
dc.subjectmutational analysisen
dc.subjectmyasthenia gravisen
dc.subjectNegroen
dc.subjectophthalmoplegiaen
dc.subjectreporter geneen
dc.subjectsequence analysisen
dc.subjectsingle nucleotide polymorphismen
dc.subjectAfrican Continental Ancestry Groupen
dc.subjectAntigens, CD55en
dc.subjectCell Line, Tumoren
dc.subjectCercopithecus aethiopsen
dc.subjectComplement Pathway, Classicalen
dc.subjectCOS Cellsen
dc.subjectImmunosuppressionen
dc.subjectLipopolysaccharidesen
dc.subjectMiceen
dc.subjectMyasthenia Gravisen
dc.subjectParesisen
dc.subjectPolymorphism, Single Nucleotideen
dc.subjectResponse Elementsen
dc.subjectTranscription, Geneticen
dc.titleA functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravisen
dc.typeArticleen
dc.contributor.departmentComputational Bioscience Research Center (CBRC)en
dc.identifier.journalGenes and Immunityen
dc.identifier.pmcidPMC2834500en
dc.eprint.versionPublisher's Version/PDFen
dc.contributor.institutionNeurology Research Group, Department of Medicine, University of Cape Town, Cape Town, South Africaen
dc.contributor.institutionDepartment of Human Biology, University of Cape Town, Cape Town, South Africaen
dc.contributor.institutionSouth African National Bioinformatics Institute, University of the Western Cape, Cape Town, South Africaen
dc.contributor.affiliationKing Abdullah University of Science and Technology (KAUST)en
kaust.authorBajic, Vladimir B.en

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