Document Detail


Maternal Mthfd1 disruption impairs fetal growth but does not cause neural tube defects in mice.
MedLine Citation:
PMID:  22378735     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
DESIGN: 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:
Anna E Beaudin; Cheryll A Perry; Sally P Stabler; Robert H Allen; Patrick J Stover
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-02-29
Journal Detail:
Title:  The American journal of clinical nutrition     Volume:  95     ISSN:  1938-3207     ISO Abbreviation:  Am. J. Clin. Nutr.     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-03-21     Completed Date:  2012-05-07     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  0376027     Medline TA:  Am J Clin Nutr     Country:  United States    
Other Details:
Languages:  eng     Pagination:  882-91     Citation Subset:  AIM; IM    
Affiliation:
Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA.
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MeSH Terms
Descriptor/Qualifier:
Aminohydrolases / deficiency*,  genetics,  metabolism
Animals
Choline / metabolism
Choline Deficiency / genetics,  metabolism
Crosses, Genetic
Disease Models, Animal
Embryo Loss / genetics,  metabolism
Female
Fetal Growth Retardation / genetics*,  metabolism
Folic Acid / blood,  metabolism*
Folic Acid Deficiency / genetics,  metabolism
Formate-Tetrahydrofolate Ligase / deficiency*,  genetics,  metabolism
Genes, Lethal
Heterozygote
Homocysteine / blood,  metabolism*
Hypoxanthine / metabolism
Maternal Nutritional Physiological Phenomena
Methylenetetrahydrofolate Dehydrogenase (NADP) / deficiency*,  genetics,  metabolism
Mice
Mice, Mutant Strains
Multienzyme Complexes / deficiency*,  genetics,  metabolism
Mutagenesis, Insertional
Neural Tube Defects / genetics,  metabolism
Pregnancy
Grant Support
ID/Acronym/Agency:
HD059120/HD/NICHD NIH HHS; R01 HD059120/HD/NICHD NIH HHS; T32-HD007445/HD/NICHD NIH HHS
Chemical
Reg. No./Substance:
0/Multienzyme Complexes; 454-28-4/Homocysteine; 59-30-3/Folic Acid; 62-49-7/Choline; 68-94-0/Hypoxanthine; 73699-18-0/formyl-methenyl-methylenetetrahydrofolate synthetase; EC 1.5.1.5/Methylenetetrahydrofolate Dehydrogenase (NADP); EC 3.5.4.-/Aminohydrolases; EC 6.3.4.3/Formate-Tetrahydrofolate Ligase
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