Structural insight into the effect of polymorphic variation on the functional dynamics of methionine synthase reductase: Implications in neural tube defects

2020 ◽  
Author(s):  
Susanta Sadhukhan ◽  
Subhajit Maity ◽  
Sandipan Chakraborty ◽  
Silpita Paul ◽  
Dinesh Munian ◽  
...  
Keyword(s):  
Neural Tube ◽  
Neural Tube Defects ◽  
Methionine Synthase ◽  
Polymorphic Variation ◽  
Methionine Synthase Reductase ◽  
Functional Dynamics ◽  
Structural Insight ◽  
Insight Into

scholarly journals Vitamin B-12 and liver activity and expression of methionine synthase are decreased in fetuses with neural tube defects

2019 ◽  
Vol 109 (3) ◽  
pp. 674-683
Author(s):  
Ma'atem B Fofou-Caillierez ◽  
Rosa-Maria Guéant-Rodriguez ◽  
Jean-Marc Alberto ◽  
Céline Chéry ◽  
Thomas Josse ◽  
...  
Keyword(s):  
Cord Blood ◽  
Neural Tube ◽  
Neural Tube Defects ◽  
Intrinsic Factor ◽  
Methionine Synthase ◽  
Vitamin B ◽  
Transcriptional Level ◽  
Gene Variant ◽  
Methionine Synthase Reductase ◽  
Vitamin B 12

ABSTRACT 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.

Transcobalamin and methionine synthase reductase mutated polymorphisms aggravate the risk of neural tube defects in humans

2003 ◽  
Vol 344 (3) ◽  
pp. 189-192 ◽  
Author(s):  
R.M. Guéant-Rodriguez ◽  
C. Rendeli ◽  
B. Namour ◽  
L. Venuti ◽  
A. Romano ◽  
...  
Keyword(s):  
Neural Tube ◽  
Neural Tube Defects ◽  
Methionine Synthase ◽  
Methionine Synthase Reductase

Analysis of methionine synthase reductase polymorphisms for neural tube defects risk association

2005 ◽  
Vol 85 (3) ◽  
pp. 220-227 ◽  
Author(s):  
Valerie B. O’Leary ◽  
James L. Mills ◽  
Faith Pangilinan ◽  
Peadar N. Kirke ◽  
Christopher Cox ◽  
...  
Keyword(s):  
Neural Tube ◽  
Neural Tube Defects ◽  
Methionine Synthase ◽  
Methionine Synthase Reductase ◽  
Risk Association

scholarly journals The role of folate and one-carbon metabolism in brain development and hydrocephalus: a literature review

2017 ◽  
Vol 2 (1) ◽  
pp. 1
Author(s):  
Z. Shehata
Keyword(s):  
Cerebrospinal Fluid ◽  
Neural Tube ◽  
Neural Tube Defects ◽  
Carbon Metabolism ◽  
Treatment Options ◽  
Methyl Donors ◽  
Novel Treatment ◽  
One Carbon Metabolism ◽  
Insight Into

Folate metabolism has been known to influence the development of the nervous system, as found in the case of neural tube defects. Folates are a group of compounds involved in one-carbon metabolism, which is necessary for the formation of purine and thymidine nucleotides, as well as methionine and methyl donors. In addition to the well-documented role of folates within the pathogenesis of neural tube defects, current literature provides evidence that folate imbalances may play a significant role in the development and effects of hydrocephalus. This review considers the possibility that folate imbalances in hydrocephalic cerebrospinal fluid may be responsible for the neurological deficit seen in patients with this condition. Understanding the details of this potential imbalance may provide further insight into novel treatment options for hydrocephalus in the future.

scholarly journals Methionine synthase and neural tube defects.

1997 ◽  
Vol 34 (11) ◽  
pp. 958-958 ◽  
Author(s):  
K Morrison ◽  
Y H Edwards ◽  
S A Lynch ◽  
J Burn ◽  
F Hol ◽  
...  
Keyword(s):  
Neural Tube ◽  
Neural Tube Defects ◽  
Methionine Synthase

scholarly journals Nuclear factor I-C disrupts cellular homeostasis between autophagy and apoptosis via miR-200b-Ambra1 in neural tube defects

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Wanqi Huang ◽  
Tianchu Huang ◽  
Yusi Liu ◽  
Jialin Fu ◽  
Xiaowei Wei ◽  
...  
Keyword(s):  
Neural Tube ◽  
Neural Tube Defects ◽  
Critical Role ◽  
Neural Tube Closure ◽  
Nuclear Factor ◽  
Cellular Homeostasis ◽  
Factor I ◽  
Nuclear Factor I ◽  
Insight Into

AbstractImpaired autophagy and excessive apoptosis disrupt cellular homeostasis and contribute to neural tube defects (NTDs), which are a group of fatal and disabling birth defects caused by the failure of neural tube closure during early embryonic development. However, the regulatory mechanisms underlying NTDs and outcomes remain elusive. Here, we report the role of the transcription factor nuclear factor I-C (NFIC) in maintaining cellular homeostasis in NTDs. We demonstrated that abnormally elevated levels of NFIC in a mouse model of NTDs can interact with the miR-200b promoter, leading to the activation of the transcription of miR-200b, which plays a critical role in NTD formation, as reported in our previous study. Furthermore, miR-200b represses autophagy and triggers apoptosis by directly targeting the autophagy-related gene Ambra1 (Autophagy/Beclin1 regulator 1). Notably, miR-200b inhibitors mitigate the unexpected effects of NFIC on autophagy and apoptosis. Collectively, these results indicate that the NFIC-miR-200b-Ambra1 axis, which integrates transcription- and epigenome-regulated miRNAs and an autophagy regulator, disrupts cellular homeostasis during the closure of the neural tube, and may provide new insight into NTD pathogenesis.

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