Molecular Genetic Basis of Williams Syndrome

威廉姆斯综合征的分子遗传学基础

• 批准号: 6624424
• 负责人: FRANK H RUDDLE
• 金额: $ 38.83万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6624424
• 关键词: Williams syndrome; antisense nucleic acid; biotechnology; gene expression; gene mutation; gene targeting; genetic mapping; genetic susceptibility; genetically modified animals; immunoprecipitation; laboratory mouse; microarray technology; molecular genetics; subtraction hybridization; transcription factor; transfection

DESCRIPTION (provided by the applicant): Williams Syndrome (WS) is an autosomal dominant genetic condition characterized by an ensemble of physical, cognitive, and behavioral traits. The syndrome has been mapped to 7ql1.23, where genetic causation is attributed to a microdeletion of approximately 1.5 Mb in length. To date, 17 genes have been identified in the haplo-insufficiency region, which serve as specific candidates for the multiple features of the condition. While the 1.5 Mb deletion occurs most commonly, smaller more informative deletions occur at a lower frequency and facilitate the presumptive identification of genes that are causal to specific cranio-facial and neurological attributes of WS. Currently, deletion mapping implicates genes near the telomeric terminus of the deletion, as most critical in phenotype causation. Three genes are viable candidates. These are CLIP-115, BEN, and TFII-I. CLIP-115 is a cytoplasmic linker protein, while TFII-I and BEN are closely related helix-loop-helix transcription factors. We have recently isolated the BEN gene in mice in a search for factors that bind to the early enhancer of the developmentally important Hoxc8 gene. This implicates BEN and TFII-I as candidate developmental factors, deficiencies of which may be expected to generate the symptomology of WS. In an effort to establish the molecular basis of WS, we will use chromosome engineering and other transgenic methodologies to simulate a haplo-insufficiency for these three candidate genes in mice. The mutant mice will be examined for physical, biochemical, and behavioral phenotypes that are typical of persons with WS. In this way, we hope to implicate definitively the three candidate genes singly or in combination as casual factors in WS. This will represent the first step in establishing the molecular genetic basis of WS. The second step will involve the discovery of downstream genes regulated by the transcription factors BEN and TFII-I. We believe certain genes in this category may be profoundly deregulated in the WS haplo-insuficiency condition, and are therefore most probably the immediate causal factors in WS. The establishment of the developmental genetic basis of WS is important beyond the understanding it brings to WS itself. The identification of genes that regulate behavior allows further investigation of genetic polymorphisms of these genes that may be causal to less severe behavioral conditions or to variations in behavior within a range considered normal.

描述(申请人提供)：威廉姆斯综合征(WS)是一种常染色体 显性遗传疾病的特征是身体上，认知上， 和行为特征。该综合征已被定位到7ql1.23，其中 原因归因于长度约1.5Mb的微缺失。 到目前为止，已经在单链缺陷区发现了17个基因，其中 作为条件的多个特征的特定候选者。而当 1.5Mb的删除是最常见的，更小、更有信息量的删除 发生的频率较低，并有助于推定识别 与特定的颅面部和神经学特征有关的基因 WS.目前，缺失图谱涉及到端粒末端附近的基因 缺失，是表型原因中最关键的。有三种基因是有活性的 候选人。它们是CLIP-115、BEN和TFII-I。CLIP-115是一种细胞质 连接蛋白，而TFII-I和BEN是紧密相关的螺旋-环-螺旋 转录因子。我们最近在小鼠体内分离出了本基因 寻找与发育早期增强剂结合的因素 重要的Hoxc8基因。这意味着本和TFII-I是发展的候选 因素，这些因素的缺陷可能会导致 WS.为了建立WS的分子基础，我们将使用染色体 工程学和其他转基因方法来模拟 这三个候选基因在小鼠中缺乏。突变的小鼠 将检查符合以下条件的物理、生化和行为表型 WS患者的典型特征。通过这种方式，我们希望最终牵连到 3个候选基因单独或组合作为WS的因果因素。这 将是建立人类免疫缺陷病毒分子遗传学基础的第一步 WS.第二步将涉及发现受 转录因子Ben和TFII-I。我们相信这里面的某些基因 类别可以在WS半不充分的情况下被深刻地解除管制， 因此，它们很可能是WS的直接原因。这个 建立WS的发育遗传学基础不仅仅是重要的 理解它会给WS本身带来好处。调控基因的鉴定 行为允许进一步研究这些基因的遗传多态 这可能是导致不太严重的行为状况或 在被认为正常的范围内的行为。