title: MTHFD1 formyltetrahydrofolate synthetase deficiency, a model for the MTHFD1 R653Q variant, leads to congenital heart defects in mice.
abstract: BACKGROUND
  A 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.
  
  
  METHODS
  Female 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.
  
  
  RESULTS
  Embryonic 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.
  
  
  CONCLUSIONS
  Deficiency of the MTHFD1 10-formyltetrahydrofolate synthetase activity in embryos is associated with increased incidence of congenital heart defects.
authors.affiliation: Departments of Human Genetics and Pediatrics, McGill University, and the Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Christensen
authors.affiliation: Departments of Human Genetics and Pediatrics, McGill University, and the Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Liyuan
authors.initials: L
authors.lastname: Deng
authors.affiliation: Departments of Human Genetics and Pediatrics, McGill University, and the Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Renata H
authors.initials: RH
authors.lastname: Bahous
authors.affiliation: Departments of Human Genetics and Pediatrics, McGill University, and the Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Loydie A
authors.initials: LA
authors.lastname: Jerome-Majewska
authors.affiliation: Departments of Human Genetics and Pediatrics, McGill University, and the Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Rima
authors.initials: R
authors.lastname: Rozen
mesh_terms: D000619:Aminohydrolases / Q000235:genetics*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005574:Formate-Tetrahydrofolate Ligase / Q000235:genetics*; D006330:Heart Defects, Congenital / Q000235:genetics*; D008297:Male; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000235:genetics*
chemical_list: D009097:Multienzyme Complexes; C021836:formyl-methenyl-methylenetetrahydrofolate synthetase; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D000619:Aminohydrolases; D005574:Formate-Tetrahydrofolate Ligase
keywords: 10-formyltetrahydrofolate synthetase; MTHFD1; congenital heart defects; folic acid; one-carbon folate metabolism; rs2236225; ventricular septal defect