Association of genomic instability, and the methylation status of imprinted genes and mismatch-repair genes, with neural tube defects

作者：Liu, Zhuo; Wang, Zhigang; Li, Yuanyuan; Ouyang, Shengrong; Chang, Huibo; Zhang, Ting; Zheng, Xiaoying; Wu, Jianxin^*

来源：European Journal of Human Genetics, 2012, 20(5): 516-520.

DOI：10.1038/ejhg.2011.242

• neural tube defects
• microsatellite instability
• mismatch repair
• methylation
• IGF2/H19

We studied the genomic instability and methylation status of the mismatch-repair (MMR) genes hMLH1 and hMSH2, and the imprinted genes H19/IGF2, in fetuses with neural tube defects (NTDs) to explore the pathogenesis of the disease. Microsatellite instability (MSI) was observed in 23 of 50 NTD patients. Five NTD patients showed high-degree MSI (MSI-H) and 18 showed low-degree MSI (MSI-L). The frequencies of mutated microsatellite loci were 3/50 (6%) for BatT-25, 10/50 (20%) for Bat-26, 3/50 (6%) for Bat34C4, 6/50 (12%) for D2S123, 4/50 (8%) for D2S119, and 3/50 (6%) for D3S1611. The promoter regions of the hMLH1 and hMSH2 genes were unmethylated in NTD patients, as determined by methylation-specific PCR. The hMLH1 and hMSH2 promoter methylation patterns, the methylation levels of H19 DMR1, and IGF2 DMR0 were detected by bisulfite sequencing PCR, sub-cloning, and sequencing. The hMSH2 promoter sequence was unmethylated, and the hMLH1 promoter showed a specific methylation pattern at two CpG sites. The methylation levels of H19 DMR1 in the NTD and control groups are 73.3%+/- 15.9 and 58.3%+/- 11.2, respectively. The methylation level of the NTD group was higher than that of the control group (Student's t-test, P<0.05). There is no significant difference in IGF2 DMR0 methylation level between the two groups. All of the results presented here suggest that genomic instability, the MMR system, and hyper-methylation of the H19 DMR1 may be correlated with the occurrence of NTDs. European Journal of Human Genetics (2012) 20, 516-520; doi:10.1038/ejhg.2011.242; published online 11 January 2012

• 出版日期2012-5
• 单位中国医学科学院北京协和医院; 北京大学; 首都儿科研究所