An estimated one fourth of all infant deaths in this country can be attributed to birth defects. Fortunately, the number of infant morbidities and mortalities has recently been dramatically reduced by the recent fortification of the food supply with folic acid. However, there is not a clear explanation for the efficacy of this fortification. There does appear to be significant evidence supporting suboptimal folate status as a risk factor for birth defects. Moreover, lack of folate can lead to the loss of methyl groups which are essential for the regulation of gene expression, especially in the developing fetus. A specialized protein, glycine N-methyltransferase (GNMT), provides regulation of methyl group supply, and if inappropriately activated can lead to loss of methyl groups. GNMT is typically not expressed until after birth;however, certain conditions are known to activate this protein. Thus, we propose to use two models, diabetes and retinoid administration, as a means to increase GNMT gene expression and determine its impact on fetal development. If GNMT can indeed be induced and result in the loss of methyl groups, this may provide a link to the occurrence of birth defects. Because folate is a methyl group provider and regulator of GNMT, this may also provide insight into the efficacy of optimal folate status and reduced incidence of birth defects. PROJECT NARRATIVE: This project is aimed at more clearly understanding the etiology of birth defects and how folate and regulation of methyl group metabolism may play a role. This knowledge will allow development of future guidelines and intervention strategies to reduce the incidence of birth defects.
