|Maternal Mthfd1 disruption impairs fetal growth but does not cause neural tube defects in mice.|
|PMID: 22378735 Owner: NLM Status: MEDLINE|
|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.
|Anna E Beaudin; Cheryll A Perry; Sally P Stabler; Robert H Allen; Patrick J Stover|
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|Type: Journal Article; Research Support, N.I.H., Extramural Date: 2012-02-29|
|Title: The American journal of clinical nutrition Volume: 95 ISSN: 1938-3207 ISO Abbreviation: Am. J. Clin. Nutr. Publication Date: 2012 Apr|
|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|
|Languages: eng Pagination: 882-91 Citation Subset: AIM; IM|
|Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA.|
|APA/MLA Format Download EndNote Download BibTex|
Choline / metabolism
Choline Deficiency / genetics, metabolism
Disease Models, Animal
Embryo Loss / genetics, metabolism
Fetal Growth Retardation / genetics*, metabolism
Folic Acid / blood, metabolism*
Folic Acid Deficiency / genetics, metabolism
Formate-Tetrahydrofolate Ligase / deficiency*, genetics, metabolism
Homocysteine / blood, metabolism*
Hypoxanthine / metabolism
Maternal Nutritional Physiological Phenomena
Methylenetetrahydrofolate Dehydrogenase (NADP) / deficiency*, genetics, metabolism
Mice, Mutant Strains
Multienzyme Complexes / deficiency*, genetics, metabolism
Neural Tube Defects / genetics, metabolism
|HD059120/HD/NICHD NIH HHS; R01 HD059120/HD/NICHD NIH HHS; T32-HD007445/HD/NICHD NIH HHS|
|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 220.127.116.11/Methylenetetrahydrofolate Dehydrogenase (NADP); EC 3.5.4.-/Aminohydrolases; EC 18.104.22.168/Formate-Tetrahydrofolate Ligase|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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