Higashimoto K, Jozaki K, Kosho T, Matsubara K, Fuke T, Yamada D, Yatsuki H, Maeda T, Ohtsuka Y, Nishioka K, Joh K, Koseki H, Ogata T, Soejima H
Division of Molecular Genetics & Epigenetics, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan.
Clin Genet. 2014 Dec;86(6):539-44. doi: 10.1111/cge.12318. Epub 2013 Dec 4.
The IGF2/H19-imprinting control region (ICR1) functions as an insulator to methylation-sensitive binding of CTCF protein, and regulates imprinted expression of IGF2 and H19 in a parental origin-specific manner. ICR1 methylation defects cause abnormal expression of imprinted genes, leading to Beckwith-Wiedemann syndrome (BWS) or Silver-Russell syndrome (SRS). Not only ICR1 microdeletions involving the CTCF-binding site, but also point mutations and a small deletion of the OCT-binding site have been shown to trigger methylation defects in BWS. Here, mutational analysis of ICR1 in 11 BWS and 12 SRS patients with ICR1 methylation defects revealed a novel de novo point mutation of the OCT-binding site on the maternal allele in one BWS patient. In BWS, all reported mutations and the small deletion of the OCT-binding site, including our case, have occurred within repeat A2. These findings indicate that the OCT-binding site is important for maintaining an unmethylated status of maternal ICR1 in early embryogenesis.
胰岛素样生长因子2/母源表达基因1印记控制区（ICR1）作为一种绝缘子，可防止CCCTC结合因子（CTCF）蛋白与甲基化敏感位点结合，并以亲本来源特异性方式调控胰岛素样生长因子2（IGF2）和母源表达基因1（H19）的印记表达。ICR1甲基化缺陷会导致印记基因表达异常，进而引发贝克威思-维德曼综合征（BWS）或罗素-西尔弗综合征（SRS）。研究表明，不仅涉及CTCF结合位点的ICR1微缺失，而且OCT结合位点的点突变和小缺失也会在BWS中引发甲基化缺陷。在此，对11例患有ICR1甲基化缺陷的BWS患者和12例SRS患者的ICR1进行突变分析，结果在1例BWS患者的母本等位基因上发现了OCT结合位点的一种新的新生点突变。在BWS中，所有已报道的突变以及包括我们病例在内的OCT结合位点小缺失均发生在重复序列A2内。这些发现表明，OCT结合位点对于维持早期胚胎发育过程中母本ICR1的未甲基化状态至关重要。
