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. 2002 Nov;71(5):1207-15.
doi: 10.1086/344213. Epub 2002 Oct 16.

A polymorphism, R653Q, in the trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase is a maternal genetic risk factor for neural tube defects: report of the Birth Defects Research Group

Lawrence C Brody  1 , Mary Conley, Christopher Cox, Peadar N Kirke, Mary P McKeever, James L Mills, Anne M Molloy, Valerie B O'Leary, Anne Parle-McDermott, John M Scott, Deborah A Swanson
Affiliations

A polymorphism, R653Q, in the trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase is a maternal genetic risk factor for neural tube defects: report of the Birth Defects Research Group

Lawrence C Brody et al. Am J Hum Genet. 2002 Nov.

Abstract

Women who take folic acid periconceptionally reduce their risk of having a child with a neural tube defect (NTD) by >50%. A variant form of methylenetetrahydrofolate reductase (MTHFR) (677C-->T) is a known risk factor for NTDs, but the prevalence of the risk genotype explains only a small portion of the protective effect of folic acid. This has prompted the search for additional NTD-associated variants in folate-metabolism enzymes. We have analyzed five potential single-nucleotide polymorphisms (SNPs) in the cytoplasmic, nicotinamide adenine dinucleotide phosphate-dependent, trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase (MTHFD1) for an association with NTDs in the Irish population. One SNP, R653Q, in this gene appears to be associated with NTD risk. We observed an excess of the MTHFD1 "Q" allele in the mothers of children with NTD, compared with control individuals. This excess was driven by the overrepresentation of QQ homozygotes in the mothers of children with NTD compared with control individuals (odds ratio 1.52 [95% confidence interval 1.16-1.99], P=.003). We conclude that genetic variation in the MTHFD1 gene is associated with an increase in the genetically determined risk that a woman will bear a child with NTD and that the gene may be associated with decreased embryo survival.

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Figures

Figure 1
Figure 1
Role of MTHFD1 in DNA synthesis. The main role for MTHFD1 (shaded) is in providing 10-formyl THF and 5,10-methylene THF for purine and pyrimidine synthesis. 10-Formyl THF can be synthesized directly from formate and THF, via the synthetase activity, or from 5,10-methenyl THF, via the cyclohydrolase activity, which is channeled from 5,10-methylene THF via the dehydrogenase activity. MTHFD1 plays an indirect role in homocysteine metabolism by providing some of the 5,10-methylene THF pool, but the major source of this is SHMT. The enzymes MTHFR and MS are directly involved in homocysteine metabolism.
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References

Electronic-Database Information

    1. Cancer Genome Anatomy Project–Genetic Annotation Initiative (CGAP-GAI), http://cgap.nci.nih.gov/ (for MTHFD1 2282 C→T [SNP 616138])
    1. Entrez, http://www.ncbi.nlm.nih.gov/Entrez/ (for MTHFD1 sequence [NT-025892])
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for MTHFR [MIM 236250] and MTHFD1 [MIM 172460])
    1. Single Nucleotide Polymorphism Database, http://www.ncbi.nlm.nih.gov/SNP/ (for MTHFD1 401 G→A [rs1950902], MTHFD1 2777 C→T [rs1803950], MTHFD1 2380 G→T [rs1803951], and MTHFR 677C→T [rs1801133])

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