Mechanisms causing imprinting defects in familial Beckwith-Wiedemann syndrome with Wilms' tumour
Mechanisms causing imprinting defects in familial Beckwith-Wiedemann syndrome with Wilms' tumour
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DOI：
10.1093/hmg/ddl448
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发表时间：
2007-02-01
影响因子：
3.5
通讯作者：
Riccio, Andrea
中科院分区：
文献类型：
--
作者：
Sparago, Angela;Russo, Silvia;Riccio, Andrea
IGF 2和H19基因的印迹表达由染色体11p15.5处的印迹中心1（IC 1）控制。这是一种甲基化敏感的染色质绝缘子，通过以亲本特异性方式结合锌指蛋白CTCF发挥作用。微缺失消除IC 1的一些CTCF靶位点（CTS）与Beckwith-Wiedemann综合征（BWS）有关。然而，这些突变与分子和临床表型之间的联系存在争议。我们已经确定了两个新的家庭与IC 1缺失，其中的个人与BWS的临床特征存在于多代。通过分析IGF 2-H19基因座的甲基化模式以及具有5种不同缺失的母亲和父亲传递的个体中的临床表型，我们证明了IC 1区域中1.4-1.8 kb缺失的母亲传递与残留CTS和BWS表型的超甲基化共分离，具有完全的遗传性，而正常表型在父系传递时观察到。虽然不能在所有情况下测定基因表达，但在IGF 2 DMR 2和H19启动子处检测到的甲基化表明IC 1超甲基化始终与IGF 2的双等位基因激活和H19的双等位基因沉默相关。将这些缺失与另一组先前报道的2.2kb缺失进行比较，表明缺失等位基因上CTS的间隔对于获得异常甲基化和临床表型的突变是至关重要的。此外，我们观察到，由缺失导致的超甲基化总是马赛克，这表明IGF 2-H19基因座的表观遗传缺陷是在合子后建立的，可能会导致身体不对称和临床表型的异质性。最后，IC 1微缺失与肾母细胞瘤的高发病率相关，这使得其分子诊断对于遗传咨询和后续肿瘤监测特别重要。
The imprinted expression of the IGF2 and H19 genes is controlled by the Imprinting Centre 1 (IC1) at chromosome 11p15.5. This is a methylation-sensitive chromatin insulator that works by binding the zinc-finger protein CTCF in a parent-specific manner. Microdeletions abolishing some of the CTCF target sites (CTSs) of IC1 have been associated with the Beckwith-Wiedemann syndrome (BWS). However, the link between these mutations and the molecular and clinical phenotypes was debated. We have identified two novel families with IC1 deletions, in which individuals with the clinical features of the BWS are present in multiple generations. By analysing the methylation pattern at the IGF2-H19 locus together with the clinical phenotypes in the individuals with maternal and those with paternal transmission of five different deletions, we demonstrate that maternal transmission of 1.4-1.8 kb deletions in the IC1 region co-segregates with the hypermethylation of the residual CTSs and BWS phenotype with complete penetrance, whereas normal phenotype is observed upon paternal transmission. Although gene expression could not be assayed in all cases, the methylation detected at the IGF2 DMR2 and H19 promoter suggests that IC1 hypermethylation is consistently associated with biallelic activation of IGF2 and biallelic silencing of H19. Comparison of these deletions with a 2.2 kb one previously reported by another group indicates that the spacing of the CTSs on the deleted allele is critical for the gain of the abnormal methylation and penetrance of the clinical phenotype. Furthermore, we observe that the hypermethylation resulting from the deletions is always mosaic, suggesting that the epigenetic defect at the IGF2-H19 locus is established post-zygotically and may cause body asymmetry and heterogeneity of the clinical phenotype. Finally, the IC1 microdeletions are associated with a high incidence of Wilms' tumour, making their molecular diagnosis particularly important for genetic counselling and tumour surveillance at follow-up.