Vitamin B-12 and liver activity and expression of methionine synthase are decreased in fetuses with neural tube defects.
5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
/ genetics
Case-Control Studies
Female
Ferredoxin-NADP Reductase
/ genetics
Fetal Diseases
/ enzymology
Folic Acid
/ analysis
Gestational Age
Humans
Liver
/ chemistry
Male
Methylenetetrahydrofolate Reductase (NADPH2)
/ genetics
Neural Tube Defects
/ embryology
Pregnancy
Vitamin B 12
/ analysis
S-adenosylmethionine
gastric intrinsic factor
methionine synthase
methylenetetrahydrofolate reductase
neural tube defects
spina bifida
vitamin B-12
Journal
The American journal of clinical nutrition
ISSN: 1938-3207
Titre abrégé: Am J Clin Nutr
Pays: United States
ID NLM: 0376027
Informations de publication
Date de publication:
01 03 2019
01 03 2019
Historique:
received:
29
03
2018
accepted:
29
10
2018
pubmed:
9
3
2019
medline:
22
1
2020
entrez:
9
3
2019
Statut:
ppublish
Résumé
The risk of neural tube defects (NTDs) is influenced by nutritional factors and genetic determinants of one-carbon metabolism. A key pathway of this metabolism is the vitamin B-12- and folate-dependent remethylation of homocysteine, which depends on methionine synthase (MS, encoded by MTR), methionine synthase reductase, and methylenetetrahydrofolate reductase. Methionine, the product of this pathway, is the direct precursor of S-adenosylmethionine (SAM), the universal methyl donor needed for epigenetic mechanisms. This study aimed to evaluate whether the availability of vitamin B-12 and folate and the expression or activity of the target enzymes of the remethylation pathway are involved in NTD risk. We studied folate and vitamin B-12 concentrations and activity, expression, and gene variants of the 3 enzymes in liver from 14 NTD and 16 non-NTD fetuses. We replicated the main findings in cord blood from pregnancies of 41 NTD fetuses compared with 21 fetuses with polymalformations (metabolic and genetic findings) and 375 control pregnancies (genetic findings). The tissue concentration of vitamin B-12 (P = 0.003), but not folate, and the activity (P = 0.001), transcriptional level (P = 0.016), and protein expression (P = 0.003) of MS were decreased and the truncated inactive isoforms of MS were increased in NTD livers. SAM was significantly correlated with MS activity and vitamin B-12. A gene variant in exon 1 of GIF (Gastric Intrinsic Factor gene) was associated with a dramatic decrease of liver vitamin B-12 in 2 cases. We confirmed the decreased vitamin B-12 in cord blood from NTD pregnancies. A gene variant of GIF exon 3 was associated with NTD risk. The decreased vitamin B-12 in liver and cord blood and decreased expression and activity of MS in liver point out the impaired remethylation pathway as hallmarks associated with NTD risk. We suggest evaluating vitamin B-12 in the nutritional recommendations for prevention of NTD risk beside folate fortification or supplementation.
Sections du résumé
BACKGROUND
The risk of neural tube defects (NTDs) is influenced by nutritional factors and genetic determinants of one-carbon metabolism. A key pathway of this metabolism is the vitamin B-12- and folate-dependent remethylation of homocysteine, which depends on methionine synthase (MS, encoded by MTR), methionine synthase reductase, and methylenetetrahydrofolate reductase. Methionine, the product of this pathway, is the direct precursor of S-adenosylmethionine (SAM), the universal methyl donor needed for epigenetic mechanisms.
OBJECTIVES
This study aimed to evaluate whether the availability of vitamin B-12 and folate and the expression or activity of the target enzymes of the remethylation pathway are involved in NTD risk.
METHODS
We studied folate and vitamin B-12 concentrations and activity, expression, and gene variants of the 3 enzymes in liver from 14 NTD and 16 non-NTD fetuses. We replicated the main findings in cord blood from pregnancies of 41 NTD fetuses compared with 21 fetuses with polymalformations (metabolic and genetic findings) and 375 control pregnancies (genetic findings).
RESULTS
The tissue concentration of vitamin B-12 (P = 0.003), but not folate, and the activity (P = 0.001), transcriptional level (P = 0.016), and protein expression (P = 0.003) of MS were decreased and the truncated inactive isoforms of MS were increased in NTD livers. SAM was significantly correlated with MS activity and vitamin B-12. A gene variant in exon 1 of GIF (Gastric Intrinsic Factor gene) was associated with a dramatic decrease of liver vitamin B-12 in 2 cases. We confirmed the decreased vitamin B-12 in cord blood from NTD pregnancies. A gene variant of GIF exon 3 was associated with NTD risk.
CONCLUSIONS
The decreased vitamin B-12 in liver and cord blood and decreased expression and activity of MS in liver point out the impaired remethylation pathway as hallmarks associated with NTD risk. We suggest evaluating vitamin B-12 in the nutritional recommendations for prevention of NTD risk beside folate fortification or supplementation.
Identifiants
pubmed: 30848279
pii: S0002-9165(22)03145-8
doi: 10.1093/ajcn/nqy340
doi:
Substances chimiques
Folic Acid
935E97BOY8
methionine synthase reductase
EC 1.18.1.-
Ferredoxin-NADP Reductase
EC 1.18.1.2
Methylenetetrahydrofolate Reductase (NADPH2)
EC 1.5.1.20
5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
EC 2.1.1.13
Vitamin B 12
P6YC3EG204
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
674-683Informations de copyright
© 2019 American Society for Nutrition.