title: 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 enzyme MTHFD1; 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) and pregnancy losses. We have generated a novel mouse model in which the MTHFD1 synthetase activity is inactivated without affecting protein expression or the other activities of this enzyme. 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 Mthfd1S(+/-) 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.
authors.affiliation: Departments of Human Genetics and Pediatrics, McGill University, and Montreal Children's Hospital site/McGill University Health Centre Research Institute, Montreal, Quebec, Canada.
authors.forename: K E
authors.initials: KE
authors.lastname: Christensen
authors.forename: L
authors.initials: L
authors.lastname: Deng
authors.forename: K Y
authors.initials: KY
authors.lastname: Leung
authors.forename: E
authors.initials: E
authors.lastname: Arning
authors.forename: T
authors.initials: T
authors.lastname: Bottiglieri
authors.forename: O V
authors.initials: OV
authors.lastname: Malysheva
authors.forename: M A
authors.initials: MA
authors.lastname: Caudill
authors.forename: N I
authors.initials: NI
authors.lastname: Krupenko
authors.forename: N D
authors.initials: ND
authors.lastname: Greene
authors.forename: L
authors.initials: L
authors.lastname: Jerome-Majewska
authors.forename: R E
authors.initials: RE
authors.lastname: MacKenzie
authors.forename: R
authors.initials: R
authors.lastname: Rozen
mesh_terms: D000619:Aminohydrolases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D002794:Choline / Q000378:metabolism; D000013:Congenital Abnormalities / Q000235:genetics; D020964:Embryo Loss; D047108:Embryonic Development / Q000235:genetics*; D005260:Female; D005492:Folic Acid / Q000378:metabolism; D005574:Formate-Tetrahydrofolate Ligase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D055879:Gene Knock-In Techniques; D014644:Genetic Variation; D006801:Humans; D002955:Leucovorin / Q000031:analogs & derivatives / Q000737:chemistry; D007958:Leukocyte Count; D008297:Male; D008715:Methionine / Q000378:metabolism; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009097:Multienzyme Complexes / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D064251:Multifunctional Enzymes / Q000235:genetics / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011248:Pregnancy Complications / Q000235:genetics* / Q000378:metabolism; D011687:Purines / Q000096:biosynthesis*
chemical_list: D009097:Multienzyme Complexes; D064251:Multifunctional Enzymes; D011687:Purines; C010161:10-formyltetrahydropteroylglutamic acid; C021836:formyl-methenyl-methylenetetrahydrofolate synthetase; D005492:Folic Acid; D008715:Methionine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D000619:Aminohydrolases; D005574:Formate-Tetrahydrofolate Ligase; D002794:Choline; D002955:Leucovorin