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Analysis of the MTHFD1 promoter and risk of neural tube defects

Carroll, Nicola, Pangilinan, Faith, Molloy, Anne M., Troendle, James, Mills, James L., Kirke, Peadar N., Brody, Lawrence C., Scott, John M. and Parle-McDermott, Anne orcid logoORCID: 0000-0002-1533-3209 (2009) Analysis of the MTHFD1 promoter and risk of neural tube defects. Human Genetics, 125 (3). pp. 247-256. ISSN 1913-0090

Genetic 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 126 bp 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 (χ 2 = 11.06, P = 0.001) and maternal (χ 2 = 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 development.
Item Type:Article (Published)
Additional Information:The original publication is available at www.springerlink.com
Uncontrolled Keywords:MTHFD1; NTD; Functional SNP; R653Q; Promoter; Folate; Folic acid; Spina Bifida;
Subjects:Biological Sciences > Genetics
DCU Faculties and Centres:DCU Faculties and Schools > Faculty of Science and Health > School of Biotechnology
Publisher:Springer Berlin / Heidelberg
Official URL:http://dx.doi.org/10.1007/s00439-008-0616-3
Use License:This item is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 3.0 License. View License
Funders:Intramural research Programme of NICHD, NIH, US, Health Research Board
ID Code:2965
Deposited On:16 Mar 2009 12:34 by Anne Parle-Mcdermott . Last Modified 16 Feb 2022 15:44

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