Beckwith-Wiedemann syndrome and associated tumors: Identification of factors essential for imprinting mechanisms

Beckwith-Wiedemann综合征(BWS)是一种与染色体11p15区相关的复杂遗传疾病，是一种具有肿瘤易感性的先天性过度生长综合征，基因组印记似乎在其中起着至关重要的作用。这些基本缺陷涉及从单基因突变到表观遗传现象的多种分子机制。由于BWS关键区的印记基因参与发育生长调节，这些基因的异常调控可能导致BWS特征过度生长、畸形和肿瘤发生。通过我们的建议，我们希望确定参与染色体11p区印迹调控的基本元件。为此，我们将使用一个大的BWS家族来确定一个假定的印记中心(IC)。同时，我们将利用Prader-Willi/Angelmann综合征患者在基因组水平上定义明确的ICs来分离参与调节15号染色体印记的(蛋白质)因子。这些发现--例如印记过程中可能必不可少的因素--将用于评估它们对BWS相关11p15区域的意义。这些努力最终应该是识别和表征与表观遗传调控机制普遍相关的DNA元件和蛋白质因子。

Beckwith-Wiedemann syndrom (BWS) - a congenital overgrowth syndrome with tumor predisposition - is a complex genetic disorder associated with chromosomal region 11p15 in which genomic imprinting seems to play an essential role. The basic defects involve multiple molecular mechanisms extending from single gene mutations to epigenetic phenomena. As imprinted genes of the BWS critical region are involved in development growth regulation, aberrant regulation of these genes could give rise to the BWS features overgrowth, malformations, and tumorgenesis. With our proposal we want to identify essential elements involved in the imprinting regulation of the chromosomal 11p-region. To this purpose, we will use a large BWS family to identify a putative imprinting center (IC). In parallel, we will take advantage of the on genomic level well defined ICs in Prader-Willi/Angelmann syndrome patients to isolate (protein) factors involved in mediating imprinting on chromosome 15. These findings - e.g. possible factors essential for the imprinting process - will be used to evaluate their significance for the BWS associated 11p15 region. These efforts should end up in the identification and characterization of DNA-elements and protein factors with general relevance for epigenetic regulatory mechanisms.