title: Maternal Mthfd1 disruption impairs fetal growth but does not cause neural tube defects in mice.
abstract: BACKGROUND
  MTHFD1 encodes C1-tetrahydrofolate synthase, which is a folate-dependent enzyme that catalyzes the formation and interconversion of folate-activated one-carbon groups for nucleotide biosynthesis and cellular methylation. A polymorphism in MTHFD1 (1958G→A) impairs enzymatic activity and is associated with increased risk of adverse pregnancy outcomes, but the mechanisms are unknown.
  
  
  OBJECTIVE
  The objective of this study was to determine whether disruption of the embryonic or maternal Mthfd1 gene or both interacts with impaired folate and choline status to affect neural tube closure, fetal growth, and fertility in mice and to investigate the underlying metabolic disruptions.
  
  
  METHODS
  Dams with a gene-trapped (gt) allele in Mthfd1 and wild-type dams were fed a control or folate- and choline-deficient AIN93G diet (Dyets Inc). Litters were examined for gross morphologic defects, crown-rump length, and resorptions. Folate status and amounts of folate-related metabolites were determined in pregnant dams.
  
  
  RESULTS
  Reduced folate and choline status resulted in severe fetal growth restriction (FGR) and impaired fertility in litters harvested from Mthfd1(gt/+) dams, but embryonic Mthfd1(gt/+) genotype did not affect fetal growth. Gestational supplementation of Mthfd1(gt/+) dams with hypoxanthine increased FGR frequency and caused occasional neural tube defects (NTDs) in Mthfd1(gt/+) embryos. Mthfd1(gt/+) dams exhibited lower red blood cell folate and plasma methionine concentrations than did wild-type dams.
  
  
  CONCLUSIONS
  Maternal Mthfd1(gt/+) genotype impairs fetal growth but does not cause NTDs when dams are maintained on a folate- and choline-deficient diet. Mthfd1(gt/+) mice exhibit a spectrum of adverse reproductive outcomes previously attributed to the human MTHFD1 1958G→A polymorphism. Mthfd1 heterozygosity impairs folate status in pregnant mice but does not significantly affect homocysteine metabolism.
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Beaudin
authors.forename: Cheryll A
authors.initials: CA
authors.lastname: Perry
authors.forename: Sally P
authors.initials: SP
authors.lastname: Stabler
authors.forename: Robert H
authors.initials: RH
authors.lastname: Allen
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Stover
mesh_terms: D000619:Aminohydrolases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002794:Choline / Q000378:metabolism; D002796:Choline Deficiency / Q000235:genetics / Q000378:metabolism; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D020964:Embryo Loss / Q000235:genetics / Q000378:metabolism; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics* / Q000378:metabolism; D005492:Folic Acid / Q000097:blood / Q000378:metabolism*; D005494:Folic Acid Deficiency / Q000235:genetics / Q000378:metabolism; D005574:Formate-Tetrahydrofolate Ligase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D005804:Genes, Lethal; D006579:Heterozygote; D006710:Homocysteine / Q000097:blood / Q000378:metabolism*; D019271:Hypoxanthine / Q000378:metabolism; D039382:Maternal Nutritional Physiological Phenomena; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009097:Multienzyme Complexes / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D016254:Mutagenesis, Insertional; D009436:Neural Tube Defects / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy
chemical_list: D009097:Multienzyme Complexes; D006710:Homocysteine; D019271:Hypoxanthine; C021836:formyl-methenyl-methylenetetrahydrofolate synthetase; D005492:Folic Acid; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D000619:Aminohydrolases; D005574:Formate-Tetrahydrofolate Ligase; D002794:Choline