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

Beckwith-Wiedemann综合征（BWS）是一种具有肿瘤倾向的先天性过度生长综合征，是一种与染色体区域11 p15相关的复杂遗传性疾病，其中基因组印记似乎起着重要作用。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控，这些基因的异常调控可引起BWS特征的过度生长、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11 p区域的印记调节的必要元素。为此，我们将使用一个大的BWS家庭，以确定一个推定的印迹中心（IC）。同时，我们将利用Prader-Willi/Angelmann综合征患者基因组水平上明确的IC来分离参与介导15号染色体上印记的（蛋白质）因子。这些发现-例如，可能的因素必不可少的印记过程-将被用来评估其意义的BWS相关的11 p15区域。这些努力应最终在鉴定和表征的DNA元素和蛋白质因子与表观遗传调控机制的一般相关性。

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.