University Children's Hospital Tübingen Pediatric Endocrinology, 72076, Tübingen, Germany.
Clin Epigenetics. 2012 Sep 18;4(1):15. doi: 10.1186/1868-7083-4-15.
Silver-Russell syndrome (SRS) is characterized by severe intrauterine and postnatal growth failure and frequent body asymmetry. Half of the patients with SRS carry a DNA hypomethylation of the imprinting center region 1 (ICR1) of the insulin-like growth factor 2 (IGF2)/H19 locus, and the clinical phenotype is most severe in these patients. We aimed to elucidate the epigenetic basis of asymmetry in SRS and the cellular consequences of the ICR1 hypomethylation.
The ICR1 methylation status was analyzed in blood and in addition in buccal smear probes and cultured fibroblasts obtained from punch biopsies taken from the two body halves of 5 SRS patients and 3 controls. We found that the ICR1 hypomethylation in SRS patients was stronger in blood leukocytes and oral mucosa cells than in fibroblasts. ICR1 CpG sites were affected differently. The severity of hypomethylation was not correlated to body asymmetry. IGF2 expression and IGF-II secretion of fibroblasts were not correlated to the degree of ICR1 hypomethylation. SRS fibroblasts responded well to stimulation by recombinant human IGF-I or IGF-II, with proliferation rates comparable with controls. Clonal expansion of primary fibroblasts confirmed the complexity of the cellular mosaicism.
We conclude that the ICR1 hypomethylation SRS is tissue, cell, and CpG site specific. The correlation of the ICR1 hypomethylation to IGF2 and H19 expression is not strict, may depend on the investigated tissue, and may become evident only in case of more severe methylation defects. The body asymmetry in juvenile SRS patients is not related to a corresponding ICR1 hypomethylation gradient, rendering more likely an intrauterine origin of asymmetry. Overall, it may be instrumental to consider not only the ICR1 methylation status as decisive for IGF2/H19 expression regulation.
银-罗素综合征（SRS）的特征是严重的宫内和产后生长发育迟缓，且经常出现身体不对称。有一半的 SRS 患者携带胰岛素样生长因子 2（IGF2）/H19 基因座印迹中心区域 1（ICR1）的 DNA 低甲基化，这些患者的临床表型最为严重。我们旨在阐明 SRS 不对称的表观遗传基础以及 ICR1 低甲基化的细胞后果。
对来自 5 名 SRS 患者和 3 名对照者的半身穿刺活检获得的血液以及口腔拭子探针和培养的成纤维细胞中的 ICR1 甲基化状态进行了分析。我们发现，与成纤维细胞相比，SRS 患者的 ICR1 低甲基化在血液白细胞和口腔黏膜细胞中更为强烈。ICR1 CpG 位点受到不同程度的影响。低甲基化的严重程度与身体不对称无关。IGF2 表达和 IGF-II 分泌与 ICR1 低甲基化的程度无关。SRS 成纤维细胞对重组人 IGF-I 或 IGF-II 的刺激反应良好，其增殖率与对照者相当。原代成纤维细胞的克隆扩增证实了细胞嵌合体的复杂性。
我们得出结论，ICR1 低甲基化 SRS 是组织、细胞和 CpG 位点特异性的。ICR1 低甲基化与 IGF2 和 H19 表达的相关性并不严格，可能取决于所研究的组织，并且只有在更严重的甲基化缺陷的情况下才变得明显。青少年 SRS 患者的身体不对称与相应的 ICR1 低甲基化梯度无关，更有可能是宫内起源的不对称。总的来说，不仅要考虑 ICR1 甲基化状态对 IGF2/H19 表达调控的决定性作用。
