BWS and Embryonal Tumor Suppressor Genes on 11p15

描述：Beckwith-Wiedemann综合征(BWS)导致产前过度生长， 中线出生缺陷和各种各样的胚胎肿瘤。我们的实验室 之前通过遗传连锁分析将BWS定位到llpl5，还 发现同一区域的频繁杂合性丢失(LOH) 胚胎肿瘤。在过去的资助期间，为了识别基因 在BWS和LOH中，我们分子克隆了一个内部和周围的基因 来自BWS的平衡生殖系染色体重排断点的聚类 被称为BWSCRJ的患者。令人惊讶的是，在这个区域内，我们至少发现了 8个被印记的基因，即显示特定基因的优先表达 亲本等位基因。其中几个基因跨越1Mb的LIP 15，显示出 BWS患者的遗传或表观遗传学改变。这些基因包括p57/KIP2， KvLQT1、H19、IGF2和LITI，一种新的反义定向未翻译RNA 我们发现的基因位于KvLQT1内，并与KvLQT1相反地印迹和转录。 这个多基因结构域本身被分成两个独立的印迹 亚域，它们之间有非印记基因。遗传互补 实验将胚胎肿瘤抑制基因映射到这个非印记的 间隔，尽管在一个新的印迹中也发现了罕见的突变 吉恩，TSSC5。 根据我们对导致BWS的特定基因改变的识别，我们 现在将确定BWS中的基因型和表型之间的关系，以及 BWS在家庭中传播的遗传学。在世界银行的协助下 麻省理工学院/怀特黑德基因组中心，我们将获得整个1.2Mb的序列 同源区，并鉴定保守基因、CpG岛和 其内其他潜在的基因间调控元件。我们将确定 这些序列在正常细胞中的功能作用，以及在 BWS患者，包括那些似乎显示出改变的印记影响的患者 整个印记基因域。我们将确定抑制基因(S) 胚胎肿瘤的生长并探讨其改变的机制， 包括异常印迹导致其中一个失活的可能性 收到。最后，我们将确定这些基因的正常功能和 使用转基因小鼠的调节序列。这些研究应该继续 提供了对这些基因在出生缺陷和 癌症，以及一个令人兴奋的物种比较方法来理解 在一个大的印迹结构域内对多个基因的调节。

DESCRIPTION: Beckwith-Wiedemann Syndrome (BWS) causes prenatal overgrowth, midline birth defects, and a wide variety of embryonal tumors. Our laboratory previously mapped BWS to llpl5 by genetic linkage analysis and also demonstrated frequent loss of heterozygosity (LOH) of the same region in embryonal tumors. In the past grant period, in order to identify the genes involved in BWS and LOH, we molecularly cloned genes within and surrounding a cluster of balanced germline chromosomal rearrangement breakpoints from BWS patients termed BWSCRJ. Surprisingly, within this region we identified at least 8 genes which are imprinted, i.e., show preferential expression of a specific parental allele. Several of these genes, which span 1 Mb of lip 15, show genetic or epigenetic alterations in BWS patients. These include p57/KIP2, KvLQT1, H19, IGF2, and LITI, a novel antisense orientation untranslated RNA that we found is within, and imprinted and transcribed oppositely to KvLQT1. This multigene domain was itself divided into two separate imprinted subdomains, with nonimprinted genes between them. Genetic complementation experiments mapped an embryonal tumor suppressor gene to this nonimprinted interval, although rare mutations were also found as well in a novel imprinted gene, TSSC5. Based on our identification of specific genetic alterations that cause BWS, we will now determine the relationship between genotype and phenotype in BWS, and the genetics of transmission of BWS in families. With the assistance of the MIT/Whitehead Genome Center, we will obtain sequence of the entire 1.2 Mb homologous region in mouse, and identify the conserved genes, CpG islands, and other potential intergenic regulatory elements within it. We will determine the functional role of these sequences in normal cells, as well as alterations in BWS patients, including those who appear to show altered imprinting affecting the entire imprinted gene domain. We will identify the gene(s) that suppress the growth of embryonal tumors and explore the mechanism of their alteration, including the possibility that aberrant imprinting leads to inactivation of one copy. Finally, we will determine the normal function of these genes and regulatory sequences using transgenic mice. These studies should continue to provide novel insights into the role of these genes in birth defects and cancer, as well as an exciting species comparative approach to understanding the regulation of multiple genes within a large imprinted domain.