Importance of folate-homocysteine homeostasis during early embryonic development

Shveta Taparia, Janee Gelineau-van Waes, Thomas H. Rosenquist, Richard H. Finnell

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1717-1727
Number of pages11
JournalClinical Chemistry and Laboratory Medicine
Volume45
Issue number12
DOIs
StatePublished - Dec 1 2007
Externally publishedYes

Fingerprint

Homocysteine
Folic Acid
Embryonic Development
Homeostasis
Neural Tube Defects
Defects
Folate Receptor 1
Genes
Congenital Heart Defects
Autoantibodies
Folate Receptor 2
Reduced Folate Carrier Protein
Embryonic Structures
Mothers
S-Adenosylmethionine
Pregnancy
Methylation
Gene Targeting
Ablation
Metabolism

All Science Journal Classification (ASJC) codes

  • Clinical Biochemistry

Cite this

Importance of folate-homocysteine homeostasis during early embryonic development. / Taparia, Shveta; Gelineau-van Waes, Janee; Rosenquist, Thomas H.; Finnell, Richard H.

In: Clinical Chemistry and Laboratory Medicine, Vol. 45, No. 12, 01.12.2007, p. 1717-1727.

Research output: Contribution to journalArticle

Taparia, Shveta ; Gelineau-van Waes, Janee ; Rosenquist, Thomas H. ; Finnell, Richard H. / Importance of folate-homocysteine homeostasis during early embryonic development. In: Clinical Chemistry and Laboratory Medicine. 2007 ; Vol. 45, No. 12. pp. 1717-1727.
@article{52e7e05515fd44148f53890b31e96442,
title = "Importance of folate-homocysteine homeostasis during early embryonic development",
abstract = "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.",
author = "Shveta Taparia and {Gelineau-van Waes}, Janee and Rosenquist, {Thomas H.} and Finnell, {Richard H.}",
year = "2007",
month = "12",
day = "1",
doi = "10.1515/CCLM.2007.345",
language = "English",
volume = "45",
pages = "1717--1727",
journal = "Clinical Chemistry and Laboratory Medicine",
issn = "1434-6621",
publisher = "Walter de Gruyter GmbH & Co. KG",
number = "12",

}

TY - JOUR

T1 - Importance of folate-homocysteine homeostasis during early embryonic development

AU - Taparia, Shveta

AU - Gelineau-van Waes, Janee

AU - Rosenquist, Thomas H.

AU - Finnell, Richard H.

PY - 2007/12/1

Y1 - 2007/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=36849064315&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=36849064315&partnerID=8YFLogxK

U2 - 10.1515/CCLM.2007.345

DO - 10.1515/CCLM.2007.345

M3 - Article

VL - 45

SP - 1717

EP - 1727

JO - Clinical Chemistry and Laboratory Medicine

JF - Clinical Chemistry and Laboratory Medicine

SN - 1434-6621

IS - 12

ER -