ISOLATION OF THE HUNTINGTON'S DISEASE GENE

该项目的长期目标是分离亨廷顿病 (HD)基因，确定导致基因突变的基因中最常见的突变。 并最终在分子水平上理解突变体 该基因座上的等位基因产生疾病的神经病理学， 杂合子 物理映射策略的组合将 用于编制一个非常高分辨率的物理地图， 大约2.5 Mb的DNA，现在似乎是最狭义的定义， 疾病基因的位置。 这将包括几种方法， 快速分离并绘制了许多新的DNA探针， 染色体带4p16.3。 保留4号染色体的体细胞杂种 从几个重要的HD重组体中分离， 广泛的特点。 这提供了一种明确的手段， 大量多态位点的单倍型分析，这将允许更多的 对疾病基因进行精确定位。 所有的DNA 将分离显示含有HD基因的最小物理区域 在重叠粘粒和YAC克隆中。 克隆的DNA将被彻底 检查以鉴定可能代表转录的基因组序列 地区 完整的lengih cDNA克隆和基因组克隆， HD基因的候选者将被分离并用于比较 这些基因在正常个体中的结构、序列和表达， HD杂合子和HD纯合子，以确定一个特定的 这是最常见的HD突变。 实现 这一目标的实现将最终导致对 正常的HD基因产生并提供洞察力， 突变基因产物紊乱 希望这些信息能指出 可以完全预防症状的发生。

The long term goals of this project are to isolate the Huntington's disease (HD) gene, identify the most common mutation in the gene which causes the disease and, ultimately, understand at the molecular level how a mutant allele at this locus produces the neuropathology of the disease in heterozygotes. A combination of physical mapping strategies will be employed to compile a very high resolution physical map of a region of about 2.5 Mb of DNA which now appears to be the most narrowly defined location of the disease gene. This will include several approaches to rapidly isolate and map many new DNA probes throughout this segment of chromosomal band 4p16.3. Somatic cell hybrids which retain chromosomes 4 from several important recombinants with HD will be isolated and extensively characterized. This provides a means for unequivocal haplotyping of a large number of polymorphic loci which will allow a more precise locilization for the disease gene to be made. All of the DNA from the minimal physical region shown to contain the HD gene will be isolated in overlapping cosmid and YAC clones. The cloned DNA will be thoroughly examined to identify genomic sequences likely to represent transcribed regions. Full lengih cDNA clones and genomic clones representing candidates for the HD gene will be isolated and used to compare the structure, sequence and expression of these genes in normal individuals, HD heterozygotes and HD homozygotes in order to identify a specific alteration which represents the most common HD mutation. The achievement of this goal will eventually lead to an understanding of the function of the normal HD gene produce and provide insight into how the presence of a mutant gene product disorder. This information will hopefully point to possible completely prevent the onset of symptoms.