Molecular Genetic Basis of Williams Syndrome

威廉姆斯综合征的分子遗传学基础

• 批准号: 6474894
• 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/6474894
• 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（由申请人提供）：威廉姆斯综合症（WS）是一种常染色体 显性遗传病的特征是身体、认知、 和行为特征。该综合征已被映射到 7ql1.23，其中遗传 因果关系归因于长度约为 1.5 Mb 的微缺失。 迄今为止，单倍体不足区域已鉴定出 17 个基因， 作为该病症的多种特征的特定候选者。尽管 1.5 Mb 删除最常见，较小的删除信息量更大 发生频率较低，有利于推定识别 与特定颅面和神经系统属性相关的基因 WS。目前，缺失图谱表明端粒末端附近的基因 缺失是表型因果关系中最关键的。三个基因都是可行的 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 是密切相关的螺旋-环-螺旋 转录因子。我们最近在小鼠体内分离出了 BEN 基因 寻找与发育早期增强子结合的因子 重要的Hoxc8基因。这意味着 BEN 和 TFII-I 作为候选发育 因素，这些因素的缺陷可能会产生以下症状 WS。为了建立 WS 的分子基础，我们将使用染色体 工程和其他转基因方法来模拟 小鼠中这三个候选基因的单倍体不足。突变小鼠 将检查物理、生化和行为表型 典型的 WS 患者。通过这种方式，我们希望明确地暗示 三个候选基因单独或组合作为 WS 的偶然因素。这 将代表建立分子遗传学基础的第一步 WS。第二步将涉及发现受调控的下游基因 转录因子 BEN 和 TFII-I。我们相信某些基因在其中 在 WS 单倍体不足的情况下，类别可能会被彻底放松管制， 因此很可能是 WS 的直接致病因素。这 建立 WS 的发育遗传基础比 理解它给 WS 本身带来的影响。调节基因的鉴定 行为允许进一步研究这些基因的遗传多态性 这可能是导致不太严重的行为状况或变化的原因 行为在被认为正常的范围内。