Squire J A, Li M, Perlikowski S, Fei Y L, Bayani J, Zhang Z M, Weksberg R
Ontario Cancer Institute, The Hospital for Sick Children, Toronto, Canada.
Genomics. 2000 May 1;65(3):234-42. doi: 10.1006/geno.2000.6155.
Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder resulting from dysregulation of multiple imprinted genes through a variety of distinct mechanisms. A frequent alteration in BWS involves changes in the imprinting status of the coordinately regulated IGF2 and H19 genes on 11p15. Patients have been categorized according to alterations in the imprinted expression, allele-specific methylation, and regional replication timing of these genes. In this work, IGF2/H19 expression, H19 DNA methylation, and IGF2 regional replication timing were studied in nine karyotypically normal BWS fibroblasts and two BWS patients with maternally inherited 11p15 chromosomal rearrangements. Informative patients (9/9) maintained normal monoallelic H19 expression/methylation, despite biallelic IGF2 expression in 6/9. Replication timing studies revealed no changes in the pattern of asynchronous replication timing for both a patient with biallelic IGF2 expression and a patient carrying an 11p15 inversion. In contrast, a patient with a chromosome 11;22 translocation and normal H19 expression/methylation exhibited partial loss of asynchrony and a shift toward earlier replication times. These results indicate that in BWS, (1) H19 imprinting alterations are less frequent than previously estimated, (2) IGF2 imprinting and H19 imprinting are not necessarily coordinated, and (3) alterations in regional replication timing are generally not correlated with either chromosomal rearrangements or the imprinting status of IGF2 and H19.
贝克威思-维德曼综合征（BWS）是一种过度生长疾病，由多种印记基因通过多种不同机制失调引起。BWS中常见的改变涉及11p15上协同调控的IGF2和H19基因印记状态的变化。患者已根据这些基因的印记表达、等位基因特异性甲基化和区域复制时间的改变进行分类。在这项研究中，对9例核型正常的BWS成纤维细胞和2例患有母系遗传的11p15染色体重排的BWS患者进行了IGF2/H19表达、H19 DNA甲基化和IGF2区域复制时间的研究。有信息价值的患者（9/9）维持正常的单等位基因H19表达/甲基化，尽管6/9患者存在双等位基因IGF2表达。复制时间研究显示，双等位基因IGF2表达的患者和携带11p15倒位的患者的异步复制时间模式均无变化。相比之下，一名患有11号与22号染色体易位且H19表达/甲基化正常的患者表现出部分异步性丧失，并向更早的复制时间转变。这些结果表明，在BWS中，（1）H19印记改变比先前估计的频率更低，（2）IGF2印记和H19印记不一定协调，（3）区域复制时间的改变通常与染色体重排或IGF2和H19的印记状态无关。
