Molecular Genetic Basis of Williams Syndrome

描述（由申请方提供）：威廉姆斯综合征（WS）是一种常染色体 显性遗传条件的特点是一个整体的身体，认知， 和行为特征该综合征已被定位于7ql1.23，其中遗传 其原因归因于长度约1.5 Mb的微缺失。 到目前为止，在单倍不足区域已经鉴定出17个基因， 作为条件的多个特征的特定候选者。而 1.5 Mb缺失最常见，更小的缺失信息量更大 以较低的频率发生，并有助于推定识别 基因是导致特定的颅面和神经属性， 目前，缺失作图涉及端粒末端附近的基因， 缺失，作为表型因果关系中最关键的。三个基因是可行的 候选人这些是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一个实验中分离出了小鼠的BEN基因。 寻找与发育早期增强因子结合的因子， Hoxc 8基因。这意味着BEN和TFII-I是候选的发展 这些因素的缺陷可能会导致 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 这三个候选基因在小鼠中的单倍不足。突变小鼠 将检查身体，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的因果因子。 将代表建立遗传学分子基础的第一步， 第二步将涉及发现下游基因的调控， 转录因子BEN和TFII-I。我们认为这其中的某些基因 在WS单倍缺陷条件下， 因此，最有可能是WS的直接因果因素。 建立WS的发育遗传基础是重要的， 理解它给WS本身带来的影响。识别调控基因 行为允许进一步调查这些基因的遗传多态性 这可能是不太严重的行为条件或变化的原因， 在正常范围内的行为。

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.