A novel de novo point mutation of the OCT-binding site in the IGF2/H19-imprinting control region in a Beckwith-Wiedemann syndrome patient
A novel de novo point mutation of the OCT-binding site in the IGF2/H19-imprinting control region in a Beckwith-Wiedemann syndrome patient
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DOI：
10.1111/cge.12318
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发表时间：
2014-12-01
影响因子：
3.5
通讯作者：
Soejima, H.
中科院分区：
文献类型：
--
作者：
Higashimoto, K.;Jozaki, K.;Soejima, H.
IGF 2/H19印迹控制区（ICR 1）作为CTCF蛋白甲基化敏感结合的绝缘子，并以亲本来源特异性方式调节IGF 2和H19的印迹表达。ICR 1甲基化缺陷导致印迹基因的异常表达，导致Beckwith-Wiedemann综合征（BWS）或Silver-Russell综合征（SRS）。不仅涉及CTCF结合位点的ICR 1微缺失，而且OCT结合位点的点突变和小缺失也已显示触发BWS中的甲基化缺陷。在此，对11例BWS和12例SRS患者的ICR 1甲基化缺陷进行突变分析，发现1例BWS患者的母体等位基因上的OCT结合位点发生了新的从头点突变。在BWS中，所有报告的突变和OCT结合位点的小缺失，包括我们的病例，都发生在重复A2内。这些研究结果表明，OCT结合位点是重要的，以维持一个未甲基化状态的母体ICR 1在早期胚胎发生。
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.