DNA hypermethylation of NOTCH2NLC in neuronal intranuclear inclusion disease: a case–control study
DNA hypermethylation of NOTCH2NLC in neuronal intranuclear inclusion disease: a case–control study
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DOI：
10.1007/s00415-022-11272-y
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发表时间：
2022-07
影响因子：
6
通讯作者：
Yuwen Cao;Wotu Tian;Jingying Wu;Xingwang Song;Lihua Cao;X. Luan
中科院分区：
文献类型：
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作者：
Yuwen Cao;Wotu Tian;Jingying Wu;Xingwang Song;Lihua Cao;X. Luan
背景NOTCH 2 NLC基因中的GGC重复扩增最近被提出通过普遍的功能获得机制（蛋白质和RNA毒性）引起神经元核内包涵体病（NIID）。然而，越来越多的证据表明，表观遗传学也可以发挥作用，在发病机制中的重复介导的disorders.MethodsIn这项研究中，使用MethylTarget测序，我们进行了定量分析的68个CpG位点的甲基化状态位于25 NIID患者和25年龄和性别匹配的健康对照的NOTCH 2NLC启动子周围。我们进一步探讨了DNA甲基化（DNAm）状态与疾病特征的相关性，并进行了受试者工作特征（ROC）analysis.ResultsDNAm水平的GGC重复序列和相邻的CpG岛NIID患者高于对照组，独立的性别和家族史。4个CpG位点（CpG_207、CpG_421、GpG_473和CpG_523）的DNAm水平与发病年龄呈负相关，7个CpG位点（CpG_25、CpG_298、CpG_336、CpG_374、CpG_411、CpG_421和CpG_473）的DNAm水平与GGC重复呈正相关。NIID患者除神经系统症状外还伴有系统症状，研究中观察到NOTCH 2NLCDNAm水平与多系统受累数量呈负相关。NOTCH 2 NLC启动子DNA m水平的ROC曲线下面积为0.733，最佳截断点为0.012。结论NOTCH 2 NLC启动子DNA m水平在NIID中存在异常，首次定量分析了DNA m水平与疾病特征的关系，为进一步探讨NIID的发病机制提供了依据。
BackgroundGGC repeat expansions inNOTCH2NLCgene have been recently proposed to cause neuronal intranuclear inclusion disease (NIID) via prevailing gain-of-function mechanism (protein and RNA toxicity). Nevertheless, increasing evidences suggest that epigenetics can also play a role in the pathogenesis of repeat-mediated disorders.MethodsIn this study, using MethylTarget sequencing, we performed a quantitative analysis of the methylation status of 68 CpG sites located around theNOTCH2NLCpromoter in 25 NIID patients and 25 age- and gender-matched healthy controls. We further explored the correlation of DNA methylation (DNAm) status with disease features and performed receiver operating characteristic (ROC) analysis.ResultsDNAm levels of GGC repeats and adjacent CpG islands were higher in the NIID patients than in controls, independent of gender and family history. DNAm levels at 4 CpG sites (CpG_207, CpG_421, GpG_473 and CpG_523) were negatively correlated with age at onset, and DNAm levels at 7 CpG sites (CpG_25, CpG_298, CpG_336, CpG_374, CpG_411, CpG_421 and CpG_473) were positively correlated with GGC repeats. NIID patients had concomitant system symptoms besides nervous system symptoms, and negative correlations betweenNOTCH2NLCDNAm levels and the number of multi-systemic involvement were observed in the study. The area under the ROC curve atNOTCH2NLCDNAm level reached to 0.733 for the best cutoff point of 0.012.ConclusionsOur findings suggested the aberrant DNAm status of theNOTCH2NLCpromoter in NIID, and we explored the link between DNAm levels and disease features quantitatively for the first time, which may help to further explore pathogenic mechanism.