Function of Genes in Williams Syndrome Deletion Region

描述（由申请人提供）：随着人类基因组计划的承诺， 在不久的将来提供所有人类基因的目录， 下一个世纪的研究是功能基因组学。的过程 在发育阶段和细胞类型中控制基因激活和抑制 具体方式是理解正常发展的基础， 发现人类疾病的原因。自发性重复微缺失 是系统研究半合子性下游效应的理想选择， 在缺失的基因中定义的一组基因。Williams-Beuren综合征（WBS），a 具有不同认知和行为特征的神经发育障碍 功能作为一个模型系统，以研究遗传和分子基础， 认知、言语、语言和视觉空间处理。WBS是由 染色体7q11.23的1.6 Mb DNA的复发性均匀缺失， 通过侧翼重复的染色体之间的染色体间或染色体内重组而产生 地区在缺失中，已经鉴定和表征了16个基因。 它们在DNA复制、染色质组装、 翻译，信号转导和作为结构蛋白。只有一个， 弹性蛋白基因与一种特殊的表现，主动脉瓣上 狭窄评估半合子对另一个人的功能影响 基因，部分缺失的人类将被鉴定，小鼠模型 在保守的同线区中产生相应的缺失， 小鼠5号染色体。转录因子靶基因与信号转导 分子将通过微阵列研究进行鉴定，比较基因表达 受影响的人类和缺失小鼠的各种组织中的模式。发展 WBS的分子表型将认知神经科学与分子 遗传学对分子途径的深入了解， 染色体缺失对特定的认知、行为和学习 残疾可能与常见的发育障碍有关，例如 注意力缺陷/多动症和自闭症，以及 了解正常的发育过程。

DESCRIPTION (provided by applicant): With the Human Genome Project promising to provide a catalog of all human genes in the near future, the main challenge of research in the next century is that of functional genomics. The processes that control gene activation and repression in a developmental-stage and cell-type specific manner are fundamental to understanding normal development and discovering the causes of human disease. Spontaneously recurring microdeletions are ideal for a systematic study of the downstream effects of hemizygosity for the defined set of genes in the deletion. Williams-Beuren syndrome (WBS), a neurodevelopmental disorder with a distinct profile of cognitive and behavioral features serves as a model system to study the genetic and molecular basis of cognition, speech, language, and visuo-spatial processing. WBS is caused by recurrent uniform deletions of 1.6 Mb of DNA from chromosome 7q11.23, that arise by inter- or intrachromosomal recombination between flanking duplicated regions. Within the deletion, 16 genes have been identified and characterized. They function as transcription factors, in DNA replication, chromatin assembly, translation, signal transduction and as structural proteins. Only one, the elastin gene has been linked to a specific manifestation, supravalvular aortic stenosis. To evaluate the functional consequences of hemizygosity for the other genes, humans with partial deletions will be identified and mouse models generated with corresponding deletions in the conserved syntenic region on mouse chromosome 5. Target genes of transcription factors and signaling molecules will be identified by microarray studies, comparing gene expression patterns in various tissues from affected humans and deletion mice. Development of a molecular phenotype of WBS links cognitive neuroscience to molecular genetics. Insights gained into the molecular pathways, that lead from the chromosomal deletion to the specific cognitive, behavioral and learning disabilities may have relevance for common developmental disorders, such as attention deficit/hyperactivity disorder and autism, as well as for understanding normal developmental processes.