MTHFD1 formyltetrahydrofolate synthetase deficiency, a model for the MTHFD1 R653Q variant, leads to congenital heart defects in mice

作者：Christensen Karen E; Deng Liyuan; Bahous Renata H; Jerome Majewska Loydie A; Rozen Rima^*

来源：Birth Defects Research Part A: Clinical and Molecular Teratology , 2015, 103(12): 1031-1038.

DOI：10.1002/bdra.23451

• MTHFD1
• 10-formyltetrahydrofolate synthetase
• folic acid
• congenital heart defects
• ventricular septal defect
• rs2236225
• one-carbon folate metabolism

BackgroundA single nucleotide polymorphism (SNP) in the synthetase domain of the trifunctional folate-dependent enzyme MTHFD1 (c.1958G>A, R653Q) has been linked to adverse pregnancy outcomes, neural tube defects, and possibly congenital heart defects. Maternal folate deficiency may also modify the risk associated with these disorders. We recently established a mouse model with a mild deficiency of 10-formyltetrahydrofolate synthetase activity in MTHFD1 (Mthfd1S(+/-) mice) to investigate disorders associated with SNPs in this gene. The effect of synthetase deficiency on embryonic heart development has not yet been examined.
MethodsFemale Mthfd1S(+/+) and (+/-) mice were placed on control and folate-deficient diets for 6 weeks before mating to Mthfd1S(+/-) males. Embryos and placentae were collected at embryonic day 14.5. Embryos were evaluated for congenital heart defects by histological examination.
ResultsEmbryonic Mthfd1S(+/-) genotype was associated with an increased incidence of heart defects, primarily ventricular septal defects. Other markers of embryonic development (crown-rump length, embryonic weight, embryonic delay, placental weight, and thickness of the ventricular myocardium) were not affected by embryonic genotype. Maternal genotype and diet did not have a significant effect on these outcomes.
ConclusionDeficiency of the MTHFD1 10-formyltetrahydrofolate synthetase activity in embryos is associated with increased incidence of congenital heart defects. Birth Defects Research (Part A) 103:1031-1038, 2015.

• 出版日期2015-12
• 单位McGill