Trolle Christian, Nielsen Morten Muhlig, Skakkebæk Anne, Lamy Philippe, Vang Søren, Hedegaard Jakob, Nordentoft Iver, Ørntoft Torben Falck, Pedersen Jakob Skou, Gravholt Claus Højbjerg
Department of Endocrinology and Internal Medicine and Medical Research Laboratories, Aarhus University Hospital, Aarhus, Denmark.
Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
Sci Rep. 2016 Sep 30;6:34220. doi: 10.1038/srep34220.
Adults with 45,X monosomy (Turner syndrome) reflect a surviving minority since more than 99% of fetuses with 45,X monosomy die in utero. In adulthood 45,X monosomy is associated with increased morbidity and mortality, although strikingly heterogeneous with some individuals left untouched while others suffer from cardiovascular disease, autoimmune disease and infertility. The present study investigates the leukocyte DNAmethylation profile by using the 450K-Illumina Infinium assay and the leukocyte RNA-expression profile in 45,X monosomy compared with karyotypically normal female and male controls. We present results illustrating that genome wide X-chromosome RNA-expression profile, autosomal DNA-methylation profile, and the X-chromosome methylation profile clearly distinguish Turner syndrome from controls. Our results reveal genome wide hypomethylation with most differentially methylated positions showing a medium level of methylation. Contrary to previous studies, applying a single loci specific analysis at well-defined DNA loci, our results indicate that the hypomethylation extend to repetitive elements. We describe novel candidate genes that could be involved in comorbidity in TS and explain congenital urinary malformations (PRKX), premature ovarian failure (KDM6A), and aortic aneurysm formation (ZFYVE9 and TIMP1).
患有45,X单体型（特纳综合征）的成年人代表了一个存活下来的少数群体，因为超过99%的45,X单体型胎儿在子宫内死亡。在成年期，45,X单体型与发病率和死亡率增加相关，尽管个体差异显著，一些人未受影响，而另一些人则患有心血管疾病、自身免疫性疾病和不孕症。本研究通过使用450K-Illumina Infinium检测法研究了45,X单体型患者的白细胞DNA甲基化谱，并与核型正常的女性和男性对照进行比较，分析了其白细胞RNA表达谱。我们展示的结果表明，全基因组X染色体RNA表达谱、常染色体DNA甲基化谱和X染色体甲基化谱能清楚地区分特纳综合征与对照。我们的结果揭示了全基因组低甲基化，大多数差异甲基化位点显示出中等水平的甲基化。与之前的研究不同，之前的研究在明确的DNA位点进行单基因座特异性分析，而我们的结果表明低甲基化延伸至重复元件。我们描述了可能与特纳综合征合并症相关的新候选基因，并解释了先天性泌尿系统畸形（PRKX）、卵巢早衰（KDM6A）和主动脉瘤形成（ZFYVE9和TIMP1）。
