Genetic Variation in Folate Metabolism Impact on Development

Folate derivatives are utilized in single-carbon transfer reactions for many critical pathways, including methionine and DNA synthesis (see Fig. 1). For example, 5,10-methylene tetrahydrofolate (5,10-methylene THF) is required for conversion of dUMP to dTMP. It can also be converted to 10formyltetrahydrofolate for the synthesis of the purine ring, or reduced to 5-methyltetrahydrofolate (5-methylTHF) for the remethylation of homocysteine to methionine. Methionine is the precursor for S-adenosymethionine (SAM), the methyl donor in numerous methylation reactions. The enzyme 5,10-methylene tetrahydrofolate reductase (MTHFR) converts 5,10-methylene THF to 5-methylTHF, thereby regulating a balance between folate required for DNA synthesis and folate required for methionine/SAM synthesis and methylation reactions. The importance of MTHFR to SAM supply is highlighted by the fact that SAM is a MTHFR inhibitor. A common sequence variant in MTHFR has been implicated in several different complex conditions, including cardiovascular disease, neural tube defects, pregnancy complications, and cancer. This chapter will review our current knowledge on the biology of MTHFR and on the developmental problems associated with this common variant in the MTHFR gene. Other relevant enzymes in the homocysteine remethylation pathway and their sequence variants will be mentioned briefly, but additional studies are required to assess their impact on development.