WILLIAMS SYNDROME--MOLECULAR GENETIC CHARACTERIZATION

我们建议开始在威廉姆斯综合征(WMS)、一种 一种罕见的遗传性疾病，通常会导致智力低下 特异相与心脏缺陷及其认知后遗症 遗传基础。在大多数情况下，WMS与半合子有关 染色体7q11.2带弹性蛋白基因周围的缺失。到最终 在WMS中确定从基因到认知的途径，我们将仔细 定义在项目中研究的患者中缺失的基因区域 I-III。因为位于缺失附近的基因的表达也可能 受影响并对表型、遗传结构有贡献 还将确定侧翼区域。消除…的缺陷 人工酵母菌WMS区的当前物理图谱 染色体(YAC)，一种使用细菌的独立方法 将使用人工染色体(BAC)。被确立为理想的工具 在分子细胞遗传学、基因组图谱和测序方面，一系列 已经定义了50个BAC，这些BAC在WMS区域内和侧翼映射。 利用这些，现在已经克隆了WMS缺失区域的一部分，即 常见缺失的大致大小已被估计，BAC密切相关 在缺失的侧翼已被识别；4)一个新的家族 仅在该染色体带中定位的重复序列已被 确定可能对造成WMS负有最终责任的人 删除。 该项目被组织成四个目标。目标1：WMS的物理地图 区域将使用末端克隆行走、聚合酶链式反应 克隆到克隆Southern分析。目标2：一个可能 包含导致WMS认知表型的基因将是 通过BAC(细菌)的荧光原位杂交确定 人工染色体)和PACS(PI人工染色体)，Southern 单拷贝DNA标记的印迹剂量分析和PCR分析 多态标记。目标3：然后将分子数据组合在一起 利用项目I-IV的临床和神经认知数据生成 WMS的表型图谱，从分子上定义染色体区域 7q11.23很可能包含一些物理和 代谢特征，以及部分智力发育迟滞和认知 功能。目标4：这些区域的基因图谱将通过以下方式分离 进行了基因的筛选和鉴定。这项工作的结果将为 为阐明认知的共同遗传起源奠定了基础。

We propose to begin to create links between Williams syndrome (WMS), a rare genetic disorder that typically results in mental retardation, a distinctive facies and a heart defect, its cognitive sequellae and its genetic basis. In most cases, WMS is associated with a hemizygous deletion around the elastin gene on chromosome band 7q11.2. To ultimately identify the pathway from genes to cognition in WMS, we will carefully define the genetic regions deleted in the patients studied in projects I-III. Because the expression of genes located near the deletion may also be affected and contribute to the phenotype, the genetic structure of the flanking regions will also be determined. To obviate the deficiencies of the current physical map of the WMS region in yeast artificial chromosomes (YACs), an independent approach employing bacterial artificial chromosomes (BACs) will be used. Established as an ideal tool for molecular cytogenetics, genome mapping and sequencing, an array of 50 BACs has been defined that map within and flanking the WMS region. Using these, a portion of the WMS deleted region has now been cloned, the approximate size of the common deletions has been estimated, BACs closely flanking the deletion have been identified; and 4) A novel family of repeated sequences mapping only in this chromosome band has been identified that may be ultimately responsible for causing the WMS deletion. The project is organized into four aims. Aim 1: A physical map of the WMS region will be constructed in BACs and PACs using end clone walking, PCR, and clone to clone Southern analysis. Aim 2: A critical region likely to contain the genes responsible for the WMS cognitive phenotype will be defined by using fluorescence in situ hybridization of BACs (bacterial artificial chromosomes) and PACs (PI artificial chromosomes), Southern blot dosage analysis of single copy DNA markers, and PCR analyses of polymorphic markers. Aim 3: The molecular data will then be combined with the clinical and neurocognitive data from projects I-IV to generate a Phenotypic Map of WMS, to define molecularly, the regions of chromosome 7q11.23 that are likely to contain the genes for some of the physical and metabolic features, and a part of the mental retardation and cognitive features. Aim 4: The genes mapping in these regions will be isolated by cDNA selection and characterized. The results of this work will lay the groundwork for elucidating the common genetic origins of cognition.