Department of Pathology, Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai 201821, P.R. China.
Department of Clinical Medicine, Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai 201821, P.R. China.
Int J Mol Med. 2019 Jan;43(1):155-166. doi: 10.3892/ijmm.2018.3945. Epub 2018 Oct 22.
Congenital hypopituitarism (CH) is a relatively rare disease that is characterized by the deficiency of one or more hormones secreted by the pituitary gland, which leads to metabolic disorders, amenorrhea and infertility. However, the underlying molecular mechanisms of CH have not yet been fully elucidated. The present study evaluated the genome‑wide methylation level of whole blood DNA in 12 patients with CH and 12 age‑matched controls using Illumina Human Methylation 450 array, in order to determine the roles of epigenetic regulation in the pathogenesis of CH. The results demonstrated that the methylation levels of 51 CpG sites were significantly different between the patients with CH and the controls. Functional enrichment analysis identified that the aberrant methylated genes were enriched in gene sets associated with metabolic or cellular process, immune system process and reproduction. In addition, two CpG sites on genes LIM domain kinase 2 (LIMK2) and piwi‑like RNA‑mediated gene silencing 2 (PIWIL2), which are involved in spermatogenesis and/or testicular development, were identified to be hypermethylated in male patients with CH. The hypermethylation of these sites was further validated in another 40 patients with CH and 40 matched controls with a quantitative bisulfite pyrosequencing method, and the methylation levels of these two loci demonstrated promising diagnostic capacities for CH. The present results suggested that aberrant methylation of genes may be involved in the pathogenesis of CH, and hypermethylation of LIMK2 and PIWIL2 may contribute to the infertility of male patients with CH. Further studies are required to elucidate the underlying mechanisms of the epigenetic regulation of these genes.
先天性垂体功能减退症 (CH) 是一种相对罕见的疾病，其特征是垂体分泌的一种或多种激素缺乏，导致代谢紊乱、闭经和不育。然而，CH 的潜在分子机制尚未完全阐明。本研究通过 Illumina Human Methylation 450 阵列评估了 12 例 CH 患者和 12 例年龄匹配对照者的全血 DNA 全基因组甲基化水平，以确定表观遗传调控在 CH 发病机制中的作用。结果表明，CH 患者与对照组之间有 51 个 CpG 位点的甲基化水平存在显著差异。功能富集分析确定，异常甲基化基因富集在与代谢或细胞过程、免疫系统过程和生殖相关的基因集。此外，在参与精子发生和/或睾丸发育的 LIM 结构域激酶 2 (LIMK2) 和 piwi 样 RNA 介导的基因沉默 2 (PIWIL2) 基因上的两个 CpG 位点在 CH 男性患者中被鉴定为过度甲基化。通过定量亚硫酸氢盐焦磷酸测序方法在另外 40 例 CH 患者和 40 例匹配对照者中进一步验证了这些位点的高甲基化，并且这两个位点的甲基化水平对 CH 具有有前途的诊断能力。本研究结果表明，基因的异常甲基化可能参与 CH 的发病机制，并且 LIMK2 和 PIWIL2 的高甲基化可能导致 CH 男性患者不育。需要进一步研究来阐明这些基因表观遗传调控的潜在机制。
