...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Clinical epigenetics. >Identification of a methylation profile for DNMT1-associated autosomal dominant cerebellar ataxia, deafness, and narcolepsy
【24h】

Identification of a methylation profile for DNMT1-associated autosomal dominant cerebellar ataxia, deafness, and narcolepsy

机译：与DNMT1相关的常染色体显性遗传性小脑共济失调，耳聋和发作性睡病的甲基化特征的鉴定

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

BackgroundDNA methylation is an essential epigenetic mark, controlled by DNA methyltransferase (DNMT) proteins, which regulates chromatin structure and gene expression throughout the genome. In this study, we describe a family with adult-onset autosomal dominant cerebellar ataxia with deafness and narcolepsy (ADCA-DN) caused by mutations in the maintenance methyltransferase DNMT1 and assess the DNA methylation profile of these individuals. ResultsWe report a family with six individuals affected with ADCA-DN; specifically, patients first developed hearing loss and ataxia, followed by narcolepsy, and cognitive decline. We identified a heterozygous DNMT1 variant, c.1709C>T [p.Ala570Val] by Sanger sequencing, which had been previously reported as pathogenic for ADCA-DN and segregated with disease in the family. DNA methylation analysis by high-resolution genome-wide DNA methylation array identified a decrease in CpGs with 0–10?% methylation and 80–95?% methylation and a concomitant increase in sites with 10–30?% methylation and >95?% methylation. This pattern suggests an increase in methylation of normally unmethylated regions, such as promoters and CpG islands, as well as further methylation of highly methylated gene bodies and intergenic regions. Furthermore, a regional analysis identified 82 hypermethylated loci with consistent robust differences across ≥5 consecutive probes compared to our large reference cohort. ConclusionsThis report identifies robust changes in the DNA methylation patterns in ADCA-DN patients, which is an important step towards elucidating disease pathogenesis.
机译：背景技术DNA甲基化是必需的表观遗传标记，受DNA甲基转移酶（DNMT）蛋白控制，该蛋白可调节整个基因组中的染色质结构和基因表达。在这项研究中，我们描述了一个由维持性甲基转移酶DNMT1突变引起的成年发作性常染色体显性遗传性小脑共济失调，耳聋和发作性睡病（ADCA-DN）的家庭，并评估了这些个体的DNA甲基化谱。结果我们报告了一个家庭，其中有6个人受到ADCA-DN的影响;具体而言，患者首先出现听力丧失和共济失调，其次是发作性睡病和认知能力下降。我们通过Sanger测序鉴定了杂合的DNMT1变体c.1709C> T [p.Ala570Val]，先前已报道其对ADCA-DN具有致病性，并与家族中的疾病隔离。通过高分辨率全基因组DNA甲基化阵列进行的DNA甲基化分析发现，甲基化为0–10％的甲基化和80-95％的甲基化的CpGs减少，而甲基化10–30％且> 95％的位点随之增加甲基化。这种模式表明正常未甲基化区域（如启动子和CpG岛）的甲基化增加，以及高度甲基化的基因体和基因间区域的进一步甲基化。此外，与我们的大型参考队列相比，区域分析确定了82个高甲基化基因座，在≥5个连续探针中具有一致的鲁棒性差异。结论本报告确定了ADCA-DN患者DNA甲基化模式的强劲变化，这是阐明疾病发病机理的重要一步。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号