Grant: Project Grant

Neural tube defects (NTD) are due to inadequate dietary folate. NTD rate has decreased via folic acid (FA) food fortification and consumption of FA-containing vitamins. A common genetic change is a 677C>T mutation in methylenetetrahydrofolate reductase (MTHFR), which generates the main circulatory folate, methyltetrahydrofolate (methylTHF). We had identified this change, present in ~ 10% of Canadians, as the first genetic risk factor for NTD and showed that it reduced activity and stability in the mutant enzyme. We also showed that methylTHF could stabilize the TT enzyme and improve function. FA reduces NTD incidence overall but it has never been shown that it reduces incidence for 677TT genotypes because clinical trials have not looked at MTHFR genotypes. Recent data suggest that methylTHF may also be useful, or even more useful than FA, to reduce NTD rate, but this has not been tested in any trial. Our goal is to determine if FA or methylTHF reduces NTD or other developmental anomalies in the 677TT genotype, using a new 677C>T mouse generated by our collaborator. We have just shown that the mutant TT mouse enzyme is similar to the human TT enzyme (reduced activity and stability, stabilized by methylTHF). We hypothesize that methylTHF will be more effective since it is the MTHFR product and can stabilize the mutant enzyme. Our aims are to first assess relevant metabolites in male and female mice of 3 genotypes (CC, CT and TT) fed diets with variable folate. We will then provide FA and methylTHF supplements to CC and TT females, mate them with CC males, and examine embryos for delays/defects; these studies will test impact of maternal TT genotype. We will perform the same experiments with CT females, mated with TT males, to examine impact of embryonic TT genotype. MTHFR activity will be measured in all aims. Our work will help to assess whether current strategies to reduce NTD are useful for 677TT women, and whether FA or methylTHF is more effective for all.