PDF(Pubmed)
Abstract：
In patients with proximal hypospadias, often no genetic cause is identified despite extensive genetic testing. Many genes involved in sex development encode transcription factors with strict timing and dosing of the gene products. We hypothesised that there might be recurrent differences in DNA methylation in boys with hypospadias and that these might differ between patients born small versus appropriate for gestational age. Genome-wide Methylated DNA sequencing (MeD-seq) was performed on 32bp LpnPI restriction enzyme fragments after RE-digestion in leucocytes from 16 XY boys with unexplained proximal hypospadias, one with an unexplained XX testicular disorder/difference of sex development (DSD) and twelve, healthy, sex- and age-matched controls. Five of seven differentially methylated regions (DMRs) between patients and XY controls were in the Long Intergenic Non-Protein Coding RNA 665 (LINC00665; CpG24525). Three patients showed hypermethylation of MAP3K1. Finally, no DMRs in XX testicular DSD associated genes were identified in the XX boy versus XX controls. In conclusion, we observed no recognizable epigenetic signature in 16 boys with XY proximal hypospadias and no difference between children born small versus appropriate for gestational age. Comparison to previous methylation studies in individuals with hypospadias did not show consistent findings, possibly due to the use of different inclusion criteria, tissues and methods.
摘要：
在近端尿道下裂患者中，尽管进行了广泛的基因检测，但通常没有发现遗传原因。参与性发育的许多基因编码转录因子，基因产物的时间和剂量严格。我们假设，尿道下裂男孩的DNA甲基化可能会反复出现差异，并且这些差异可能在出生时较小的患者与适合胎龄的患者之间有所不同。全基因组甲基化DNA测序（MeD-seq）在RE消化后对来自16名不明原因近端尿道下裂男孩的白细胞中的32bpLpnPI限制性内切酶片段进行了，一位患有不明原因的XX睾丸疾病/性发育差异（DSD）和十二位，健康,性别和年龄匹配的对照。患者和XY对照之间的七个差异甲基化区域(DMRs)中的五个在长基因间非蛋白编码RNA665(LINC00665;CpG24525)中。3例患者显示MAP3K1甲基化过度。最后,在XX男孩和XX对照中,没有发现XX睾丸DSD相关基因的DMRs。总之,我们在16例XY近端尿道下裂的男孩中没有观察到可识别的表观遗传特征,出生时小与适合胎龄的儿童之间没有差异.与先前在尿道下裂患者中的甲基化研究相比，没有显示出一致的发现。可能是由于使用了不同的纳入标准，组织和方法。
