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胚胎性肿瘤。本实验室 先前通过遗传连锁分析将BWS定位到11 p15， 结果表明，在同一区域的杂合性丢失（洛）， 胚胎性肿瘤在过去的资助期内，为了确定基因 参与BWS和洛缺失，我们分子克隆基因内和周围的一个 来自BWS的平衡生殖系染色体重排断裂点簇 患者称为BWSCRJ。令人惊讶的是，在这个区域内，我们至少发现了 8个基因是印记，即，表现出特定的优先表达 亲本等位基因这些基因中的几个，跨越1 Mb的唇15，显示 BWS患者的遗传或表观遗传改变。这些包括p57/KIP 2， KvLQT 1、H19、IGF 2和LITI，一种新的反义定向非翻译RNA 我们发现它就在KvLQT 1的内部，并且与KvLQT 1相反地进行印记和转录。 这个多基因域本身被分成两个独立的印记 亚结构域，它们之间有非印记基因。遗传互补 实验将一个胚胎肿瘤抑制基因定位到这个非印记基因上， 间隔，虽然罕见的突变也被发现，以及在一个新的印记 基因TSSC 5。 基于我们对导致BWS的特定遗传变异的鉴定，我们 现在将确定BWS中基因型和表型之间的关系， BWS家族传播的遗传学。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1.2 Mb的序列 同源区域，并确定保守基因，CpG岛， 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 BWS患者，包括那些表现出改变的印记影响 整个印记基因区域我们将识别抑制 胚胎性肿瘤的生长，并探讨其变化机制， 包括异常印记导致一个基因失活的可能性， 收到最后，我们将确定这些基因的正常功能， 使用转基因小鼠的调节序列。这些研究应继续下去， 为这些基因在出生缺陷中的作用提供了新的见解， 癌症，以及一个令人兴奋的物种比较方法，以了解 在一个大的印记区域内调节多个基因。

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.