Importance of folate-homocysteine homeostasis during early embryonic development.
Although the beneficial effects of maternal folate supplementation in the periconceptional period have been shown to prevent neural tube defects, congenital heart defects and orofacial clefts, the exact protective mechanism of folates remains unknown. Folates affect DNA synthesis, amino acid metabolism and methylation of genes, proteins and lipids via S-adenosylmethionine-mediated one-carbon transfer reactions. Our laboratory has created several mouse knock out models of folate transport using gene targeting to inactivate folate receptor 1 (Folr1), folate receptor 2 (Folr2) and reduced folate carrier 1 (Slc19a1) genes. Gene ablation of both Folr1 and Slc19a1 leads to lethality, but with maternal folate supplementation, nullizygous embryos for both genes present with neural tube defects (NTDs) and congenital heart defects (CHDs). Folr1 nullizygous mice also exhibit orofacial clefts when the dams are provided with low folate supplementation during pregnancy. Finally, women with NTD-affected pregnancies have been reported to have high autoantibody titers against the folate receptor, potentially inhibiting the transport of folate to the developing embryo. This may be an explanation for some of the folate-responsive NTDs and perhaps other congenital malformations. Herein, we propose how homocysteinylation of the folate receptor may contribute to generation of these autoantibodies against the folate receptor.
Taparia
Shveta
S
Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA.
Gelineau-van Waes
Janée
J
Rosenquist
Thomas H
TH
Finnell
Richard H
RH
D000818:Animals; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism; D001692:Biological Transport; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D047108:Embryonic Development; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000008:administration & dosage / Q000378:metabolism*; D006706:Homeostasis; D006710:Homocysteine / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016742:Preconception Care; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D001323:Autoantibodies; D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D011956:Receptors, Cell Surface; D006710:Homocysteine; D005492:Folic Acid