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dc.contributor.authorSCOTT, JOHNen
dc.contributor.authorMOLLOY, ANNEen
dc.date.accessioned2015-12-09T11:37:58Z
dc.date.available2015-12-09T11:37:58Z
dc.date.issued2009en
dc.date.submitted2009en
dc.identifier.citationCarroll, N., Pangilinan, F., Molloy, A.M., Troendle, J., Mills, J.L., Kirke, P.N., Brody, L.C., Scott, J.M., Parle-McDermott, A., Analysis of the MTHFD1 promoter and risk of neural tube defects, Human Genetics, 125, 3, 2009, 247, 256en
dc.identifier.otherYen
dc.identifier.urihttp://hdl.handle.net/2262/75148
dc.descriptionPUBLISHEDen
dc.description.abstractGenetic variants in MTHFD1 (5,10-methylenetetrahydrofolate dehydrogenase/ 5,10-methenyltetrahydrofolate cyclohydrolase/ 10-formyltetrahydrofolate synthetase), an important folate metabolic enzyme, are associated with a number of common diseases, including neural tube defects (NTDs). This study investigates the promoter of the human MTHFD1 gene in a bid to understand how this gene is controlled and regulated. Following a combination of in silico and molecular approaches, we report that MTHFD1 expression is controlled by a TATA-less, Initiator-less promoter and transcription is initiated at multiple start sites over a 126bp region. We confirmed the presence of three database polymorphisms (dbSNP) by direct sequencing of the upstream region (rs1076991 C>T, rs8010584 G>A, rs4243628 G>T), with a fourth (dbSNP rs746488 A>T) not found to be polymorphic in our population and no novel polymorphisms identified. We demonstrate that a common SNP rs1076991 C>T within the window of transcriptional initiation exerts a significant effect on promoter activity in vitro. We investigated this SNP as a potential risk factor for NTDs in a large homogenous Irish population and determined that it is not an independent risk factor, but, it does increase both case (χ2 = 11.06, P = 0.001) and maternal (χ2 = 6.68, P = 0.01) risk when allele frequencies were analysed in combination with the previously identified disease-associated p.R653Q (c.1958 G>A; dbSNP rs2236225) polymorphism. These results provide the first insight into how MTHFD1 is regulated and further emphasise its importance during embryonic developmenen
dc.description.sponsorshipWe wish to thank the Irish Association for Spina Bifida and Hydrocephalus and the Public Health Nurses for assistance with subject recruitment and the following Dublin maternity hospitals for control recruitment: National Maternity Hospital Holles street, the Coombe Womens' Hospital and the Rotunda Hospital. This research was supported by the Intramural Research Program of the NICHD, NIH and the Health Research Board of Ireland. Approval was obtained from the Research Ethics Committee of the Health Research Board, Ireland and the Institutional Review Board at the National Institutes of Health. All research participants provided informed consent.en
dc.format.extent247en
dc.format.extent256en
dc.relation.ispartofseriesHuman Geneticsen
dc.relation.ispartofseries125en
dc.relation.ispartofseries3en
dc.rightsYen
dc.subjectMTHFD1, NTD, Functional, SNP, R653Q, Promoteren
dc.subject.lcshMTHFD1, NTD, Functional, SNP, R653Q, Promoteren
dc.titleAnalysis of the MTHFD1 promoter and risk of neural tube defectsen
dc.typeJournal Articleen
dc.type.supercollectionscholarly_publicationsen
dc.type.supercollectionrefereed_publicationsen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/amolloyen
dc.identifier.rssinternalid59367en
dc.identifier.doihttp://dx.doi.org/10.1007/s00439-008-0616-3en
dc.rights.ecaccessrightsopenAccess
dc.subject.TCDThemeGenes & Societyen


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