Discordant KCNQ1OT1 imprinting in sets of monozygotic twins discordant for Beckwith-Wiedemann syndrome
Discordant KCNQ1OT1 imprinting in sets of monozygotic twins discordant for Beckwith-Wiedemann syndrome
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DOI：
10.1093/hmg/11.11.1317
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发表时间：
2002-05-15
影响因子：
3.5
通讯作者：
Squire, J
中科院分区：
文献类型：
--
作者：
Weksberg, R;Shuman, C;Squire, J
Beckwith-Wiedemann综合征(BWS)以内脏肿大、巨舌症、肿瘤易感性等先天异常为主要表现，常伴有11p15染色体异常。据报道，许多同卵双胞胎，大多数是女性，对BWS来说是不协调的。我们在这里显示，在BWS患者中，女性单卵双胞胎的发生率比普通人群显著增加。11p15内的一组印记基因被认为是通过KCNQ1OT1的印记表达来协调调控的，KCNQ1OT1编码未翻译的RNA。在5对与BWS不一致的同卵双胞胎的皮肤成纤维细胞中，每对患病双胞胎在11p15的KCNQ1OT1处都有印记缺陷，而未受影响的双胞胎没有。另外五对仅有血液可用的同卵双胞胎，也显示出KCNQ1OT1的印记缺陷。MZ双胞胎中BW的不一致可能是由于双胞胎期间内细胞团的不均匀分裂，从而导致KCNQ1OT1处印记的差异维持。或者，我们认为KCNQ1OT1特别容易发生印记事件的丢失，这是由于在植入前发育的关键阶段缺乏维持DNA甲基化所致，并且这种印记丢失倾向于双胞胎以及BWS的不协调。这些数据强调了对影响植入前胚胎的辅助生殖技术出生的儿童进行持续监测的重要性。
Beckwith-Wiedemann syndrome (BWS) presents with visceromegaly, macroglossia, tumor predisposition and other congenital abnormalities, and is usually associated with abnormalities of chromosome 11p15. A number of identical twin pairs, mostly female, have been reported to be discordant for BWS. We show here that the incidence of female monozygotic twins among patients with BWS is dramatically increased over that of the general population. A cluster of imprinted genes within 11p15 is thought to be coordinately regulated via the imprinted expression of KCNQ1OT1, which encodes an untranslated RNA. In skin fibroblasts from five monozygotic twin pairs discordant for BWS, each affected twin had an imprinting defect at KCNQ1OT1 on 11p15, whereas the unaffected twin did not. Five additional monozygotic twin pairs, for whom only blood was available, also displayed an imprinting defect at KCNQ1OT1. It is possible that discordance for BWS in MZ twins is due to unequal splitting of the inner cell mass during twinning, thereby causing differential maintenance of imprinting at KCNQ1OT1. Alternatively, we propose that KCNQ1OT1 is especially vulnerable to a loss of imprinting event, caused by a lack of maintenance DNA methylation at a critical stage of preimplantation development, and that this loss of imprinting predisposes to twinning as well as to discordance for BWS. These data underscore the importance of continued surveillance of children born following assisted reproductive technologies that impact the preimplantation embryo.