Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, No. 2, Yabao Road, Chao Yang District, Beijing 100020, People's Republic of China.
Mol Cell Biochem. 2013 Aug;380(1-2):33-42. doi: 10.1007/s11010-013-1655-1. Epub 2013 May 21.
Neural tube defects (NTDs) are serious congenital malformation of fusion failure of the neural tube during early embryogenesis. DNA methylation disorders have been found in NTD-affected fetuses, and are correlated to the risk of NTDs. The insulin-like growth factor 2 (IGF2) gene, maternally imprinted, has a key role in fetal development. IGF2 transcription is partly controlled by differentially methylated regions (DMRs) 0 and 2. To assess whether disturbed methylation pattern increases the incidence of NTDs, we employed matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) to quantify CpG methylation levels of DMR2 and 0 in fetuses with or without NTDs. We found that the methylation level of IGF2 DMR0 increased significantly in the brain tissues of NTD-affected fetuses. And hypermethylation of DMR0 was associated with an increased risk of NTDs, with an odds ratio of 5.375 (95 % CI: 1.447-19.965; p = 0.007). IGF2 mRNA expression was negatively correlated with the methylation level of DMR0 (R (2) = 0.893; p = 0.000) in HCT15 cells. These results highlights that IGF2 DMR0 hypermethylation is a potential risk factor of NTD, and IGF2 gene is a promising candidate gene to study for a greater understanding of the cause of NTDs.
神经管缺陷（NTDs）是胚胎早期神经管融合失败导致的严重先天性畸形。在受 NTD 影响的胎儿中发现了 DNA 甲基化紊乱，并且与 NTD 的风险相关。胰岛素样生长因子 2（IGF2）基因是母系印记的，在胎儿发育中起关键作用。IGF2 的转录部分受差异甲基化区域（DMR）0 和 2 控制。为了评估甲基化模式的紊乱是否会增加 NTD 的发生率，我们采用基质辅助激光解吸电离飞行时间质谱（MALDI-TOF MS）来定量 NTD 胎儿和无 NTD 胎儿中 DMR2 和 0 的 CpG 甲基化水平。我们发现，NTD 胎儿脑组织中 IGF2 DMR0 的甲基化水平显著增加。并且 DMR0 的高甲基化与 NTD 的风险增加相关，优势比为 5.375（95%CI：1.447-19.965;p=0.007）。在 HCT15 细胞中，IGF2mRNA 表达与 DMR0 的甲基化水平呈负相关（R2=0.893;p=0.000）。这些结果表明，IGF2 DMR0 的高甲基化是 NTD 的一个潜在危险因素，IGF2 基因是研究 NTD 病因的一个有前途的候选基因。
