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

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.

Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia

“…29 With regard to the MTHFD1 polymorphism, its functional role in folate pool maintenance has been suggested: women with the MTHFD1 AA1958 genotype were found to be at an increased risk of having NTD-affected offspring. 18 In addition, the conservation of an arginine residue at the corresponding position of the MTHFD1 gene across numerous species suggests that replacement with glutamine, caused by a G to A base substitution, may have functional consequences. 18 Since MTHFD1 arg653gln replacement lies within the 10-formyl-THF synthase domain of MTHFD1, it is possible that a reduction in 10-formyl THF formation could shift folate balance towards 5,10-methylene-THF pools required for TS synthesis.…”

“…18 In addition, the conservation of an arginine residue at the corresponding position of the MTHFD1 gene across numerous species suggests that replacement with glutamine, caused by a G to A base substitution, may have functional consequences. 18 Since MTHFD1 arg653gln replacement lies within the 10-formyl-THF synthase domain of MTHFD1, it is possible that a reduction in 10-formyl THF formation could shift folate balance towards 5,10-methylene-THF pools required for TS synthesis. In addition, genomic imbalance corresponding to the MTHFD1 locus was found in MTXresistant T-cell ALL cell lines.…”

“…17 The role of an MTHFD1 A1958 variant in NTD susceptibility suggested the possibility of its functional impact. 18 Since MTHFR and MTHFD1 polymorphisms might affect MTX sensitivity through their impact on 5-methyl-THF and 5,10-methylene-THF levels, we assessed here the association of these polymorphisms with event-and disease-free survival (EFS and DFS), overall survival (OS), as well as with the frequency of weeks with MTX dose reduction or withdrawal in children who received this drug for the treatment of ALL. Given that MTX polyglutamates directly inhibit folate-dependent enzymes, 19,20 along with the fact that thymidylate synthase (TS) requires for its activity 5,10-methylene-THF, 11,21,22 it is possible that increased levels of this cofactor, produced by altered MTHFR and/or MTHFD1 action, might facilitate thymidylate synthesis thus interfering with MTX action.…”

Evaluation of a methylenetetrahydrofolate-dehydrogenase 1958G>A polymorphism for neural tube defect risk

“…The second change, a 1958G>A substitution polymorphism resulting in replacement of the arginine residue at position 653 by glutamine (R653Q), turned out to be present in both patients and controls with similar frequencies. More recently, Brody et al (2002) demonstrated that MTHFD1 1958G>A polymorphism is a maternal risk factor for NTD risk in the Irish population. Mothers who possess two copies of the MTHFD1 1958A allele have an increased risk of an NTD-affected pregnancy.…”

“…Mothers who possess two copies of the MTHFD1 1958A allele have an increased risk of an NTD-affected pregnancy. There was also a suggestion that the MTHFD1 1958A allele decreases fetal viability (Brody et al 2002).…”