Grant: Operating Grant

Low dietary folate has been well-established as a risk factor for the development of birth defects and cancer. Variations in folate pathway genes have been identified that also increase the risk for these disorders. Folate is required to provide the building blocks for DNA and protein synthesis. The relationship between folate, birth defects and cancer may reflect the increased demand for folate pathway products in rapidly dividing cells. The MTHFD1 R653Q variant is a sequence change in an important enzyme of folate metabolism and may be a risk factor for neural tube defects (NTD), pregnancy complications and gastric cancer. We have found that the R653Q variant decreases the stability of the protein and disrupts folate metabolism in cells. The effects of the variant may be modulated by the diet or by the presence of other folate pathway variants. In this project we propose to use a mouse model to investigate the effects of MTHFD1 variants on the development of birth defects and cancer. This mouse model will allow the investigation of dietary and genetic factors not possible in human studies. Our work will further the understanding of folate metabolism and the mechanisms of the development of folate-related birth defects and cancers. This work may produce recommendations for diet and/or genetic screening for birth defects and cancer prevention.