Low folate concentration impacts mismatch repair deficiency in neural tube defects.

低叶酸浓度影响神经管缺陷中的错配修复缺陷。

• 影响指数: 4.357
• 发表时间: 01 2020
• 来源期刊: Epigenomics
• DOI: 10.2217/epi-2019-0279
• PMID: 31769301
• 文章类型: Journal Article
• 中科院分区: Q3
• 方向: 生物
• 作者列表: Li H,Wang X,Zhao H,Wang F,Bao Y,Guo J,Chang S,Wu L,Cheng H,Chen S,Zou J,Cui X,Niswander L,Finnell RH,Wang H,Zhang T

关键词: DNA repair; H3K36me3; Msh6; folate insufficiency; histone modification; mismatch repair deficiency; neural tube closure; neural tube defect; rare variant; sequencing

Mesh: DNA Mismatch Repair / genetics; Disease Susceptibility; Folic Acid / metabolism; Folic Acid Deficiency / complications metabolism; Genetic Variation; Histones / metabolism; Humans; Neural Tube Defects / etiology metabolism

Abstract

Aim: To know the cause of sequence variants in neural tube defect (NTD). Materials & methods: We sequenced genes implicated in neural tube closure (NTC) in a Chinese cohort and elucidated the molecular mechanism-driving mutations. Results: In NTD cases, an increase in specific variants was identified, potentially deleterious rare variants harbored in H3K36me3 occupancy regions that recruits mismatch repair (MMR) machinery. Lower folate concentrations in local brain tissues were also observed. In neuroectoderm cells, folic acid insufficiency attenuated association of Msh6 to H3K36me3, and reduced bindings to NTC genes. Rare variants in human NTDs were featured by MMR deficiency and more severe microsatellite instability. Conclusion: Our work suggests a mechanistic link between folate insufficiency and MMR deficiency that correlates with an increase of rare variants in NTC genes.

摘要

目的：了解神经管缺陷（NTD）序列变异的原因。材料与方法：我们对一个中国队列中涉及神经管闭合（NTC）的基因进行了测序，并阐明了驱动突变的分子机制。结果：在NTD病例中，确定了特定变体的增加，H3K36me3占用区域中存在潜在有害的稀有变体，可招募不匹配修复（MMR）机械。在局部脑组织中也观察到较低的叶酸浓度。在神经外胚层细胞中，叶酸不足减弱了Msh6与H3K36me3的关联，并减少了与NTC基因的结合。人类NTD中的罕见变异以MMR缺乏和更严重的微卫星不稳定性为特征。结论：我们的工作表明叶酸不足和MMR缺乏之间的机制联系，与NTC基因中罕见变异的增加相关。