PMID- 37424722
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230718
IS  - 1664-8021 (Print)
IS  - 1664-8021 (Electronic)
IS  - 1664-8021 (Linking)
VI  - 14
DP  - 2023
TI  - Double whammy: the genetic variants in CECR2 and high Hcy on the development of 
      neural tube defects.
PG  - 1189847
LID - 10.3389/fgene.2023.1189847 [doi]
LID - 1189847
AB  - Introduction: Neural tube defects (NTDs) are serious congenital malformations. 
      The etiology of NTDs involves both genetic and environmental factors. Loss of 
      CECR2 in mice has been shown to result in NTDs. Our previous study indicated that 
      high homocysteine (HHcy) levels could further reduced the expression level of 
      CECR2. This investigation aims to explore the genetic influence of the chromatin 
      remodeling gene, CECR2, in humans and determine if HHcy can have a synergistic 
      effect on protein expression. Methods: We conducted Next-Generation Sequencing 
      (NGS) of the CECR2 gene in 373 NTD cases and 222 healthy controls, followed by 
      functional assay application to select and evaluate CECR2 missense variants and 
      subsequent Western blotting to identify protein expression levels. Results: From 
      the analysis, we identified nine rare, NTD-specific mutations within the CECR2 
      gene. Significantly, four missense variants (p.E327V, p.T521S, p.G701R, and 
      p.G868R) were selected via functional screening. The E9.5 mouse ectodermal stem 
      cell line NE-4C, transfected with plasmids expressing p.E327V, p.T521S, p.G868R 
      variants or a recombinant harboring all four (named as 4Mut), exhibited notable 
      reductions in CECR2 protein expression. Furthermore, exposure to homocysteine 
      thiolactone (HTL), an extremely reactive homocysteine metabolite, amplified the 
      reduction in CECR2 expression, accompanied by a significant increase in the 
      apoptotic molecule Caspase3 activity, a potential NTD inducer. Importantly, folic 
      acid (FA) supplementation effectively counteracted the CECR2 expression decline 
      induced by CECR2 mutation and HTL treatment, leading to reduced apoptosis. 
      Discussion: Our observations underscore a synergistic relationship between HHcy 
      and genetic variations in CECR2 concerning NTDs, thereby reinforcing the concept 
      of gene-environment interaction phenomena in NTD etiology.
CI  - Copyright (c) 2023 Bai, Jiang, Liu, Liu and Zhang.
FAU - Bai, Baoling
AU  - Bai B
AD  - Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital 
      Institute of Pediatrics, Beijing, China.
FAU - Jiang, Qian
AU  - Jiang Q
AD  - Department of Medical Genetics, Capital Institute of Pediatrics, Beijing, China.
FAU - Liu, Lingyun
AU  - Liu L
AD  - Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital 
      Institute of Pediatrics, Beijing, China.
FAU - Liu, Changyun
AU  - Liu C
AD  - Department of Pediatrics, Weifang Medical University, Weifang, Shandong, China.
FAU - Zhang, Qin
AU  - Zhang Q
AD  - Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital 
      Institute of Pediatrics, Beijing, China.
LA  - eng
PT  - Journal Article
DEP - 20230622
PL  - Switzerland
TA  - Front Genet
JT  - Frontiers in genetics
JID - 101560621
PMC - PMC10324518
OTO - NOTNLM
OT  - CECR2
OT  - apoptosis
OT  - homocysteine
OT  - mutation
OT  - neural tube defects
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2023/07/10 06:42
MHDA- 2023/07/10 06:43
PMCR- 2023/06/22
CRDT- 2023/07/10 04:46
PHST- 2023/04/06 00:00 [received]
PHST- 2023/06/14 00:00 [accepted]
PHST- 2023/07/10 06:43 [medline]
PHST- 2023/07/10 06:42 [pubmed]
PHST- 2023/07/10 04:46 [entrez]
PHST- 2023/06/22 00:00 [pmc-release]
AID - 1189847 [pii]
AID - 10.3389/fgene.2023.1189847 [doi]
PST - epublish
SO  - Front Genet. 2023 Jun 22;14:1189847. doi: 10.3389/fgene.2023.1189847. eCollection 
      2023.