A novel mouse model for genetic variation in 10-formyltetrahydrofolate synthetase exhibits disturbed purine synthesis with impacts on pregnancy and embryonic development

Abstract

Genetic variants in one-carbon folate metabolism have been identified as risk factors for disease because they may impair the production or use of one-carbon folates required for nucleotide synthesis and methylation. p. R653Q (1958G>A) is a single-nucleotide polymorphism (SNP) in the 10-formyltetrahydrofolate (formylTHF) synthetase domain of the trifunctional enzymeMTHFD1; this domain produces the formylTHF which is required for the de novo synthesis of purines. Approximately 20% of Caucasians are homozygous for the Q allele. MTHFD1 p. R653Q has been proposed as a risk factor for neural tube defects (NTDs), congenital heart defects (CHDs)andpregnancylosses. WehavegeneratedanovelmousemodelinwhichtheMTHFD1synthetaseactivity is inactivated without affecting proteinexpression or the other activities of thisenzyme. Complete loss of synthetase activity (Mthfd1S-/-) is incompatible with life; embryos die shortly after 10.5 days gestation, and are developmentally delayed or abnormal. The proportion of 10-formylTHF in the plasma and liver of Mthfd1S+/- mice is reduced (P < 0.05), and de novo purine synthesis is impaired in Mthfd1S+/- mouse embryonic fibroblasts (MEFs, P < 0.005). Female Mthfd1S1/- mice had decreased neutrophil counts (P < 0.05) during pregnancy and increased incidence of developmental defects in embryos (P = 0.052). These findings suggest that synthetase deficiency may lead to pregnancy complications through decreased purine synthesis and reduced cellular proliferation. Additional investigation of the impact of synthetase polymorphisms on human pregnancy is warranted. © The Author 2013. Published by Oxford University Press. All rights reserved.