ISOLATION OF THE HUNTINGTON'S DISEASE GENE

本提案的长期目标是了解 遗传性神经系统疾病的分子和生物化学基础 亨廷顿氏病（Huntingtons Disease，HD） 在大多数情况下， 遗传性神经系统疾病，没有什么是已知的 HD的生化基础或受影响基因的性质。 的 只有真实的希望了解疾病和发展 有效的治疗方法，是分离和表征正常的， 缺陷等位基因 该项目的主要目的是分离 HD基因，采用反向遗传学策略。 大量的单拷贝DNA片段从远端 4号染色体短臂的一部分， HD基因已定位，已分离，将进行区域定位 使用体细胞杂交，并用于编译一个长范围的 限制性内切酶图谱的数百万个碱基对的DNA周围的 HD基因。 DNA片段靠近，并在相反的两侧 将使用几种方法鉴定HD基因。 单个 跨越含有HD基因的区域的拷贝DNA片段 将进行分析，以确定哪些代表部分 表达的基因以及是否检测到DNA序列 HD患者的重排。 基因组和cDNA克隆 代表HD基因附近的表达基因将 以确定其表达和/或结构是否 改变了患者的病情。 如果发现这种变化， 候选基因将从基因组DNA文库中分离 从HD患者和结构和序列相比， 未受影响个体的相应基因。 HD基因的分离及其功能的研究 将提供100%准确的临床前诊断能力 这种晚期发病的疾病，很可能导致 开发有效的治疗方法，以预防或延迟 症状

The long term objective of this proposal is to understand the molecular and biochemical basis for the inherited neurological disorder, Huntingtons Disease (HD). As in the case with most inherited neurologic disorders, nothing is known about the biochemical basis of HD or the nature of the affected gene. The only real hope of understanding the disease and developing effective therapies, is to isolate and characterize the normal and defective alleles. The major aim of this project is to isolate the HD gene, using the strategy of reverse genetics. A large number of single copy DNA fragments from the distal portion of the short arm of chromosome 4, the region where the HD gene is located, have been isolated, will be regionally mapped using somatic cell hybrids, and used to compile a long range restriction map of several million base pairs of DNA around the HD gene. DNA fragments that are close to, and on opposite sides of the HD gene will be identified using several approaches. Single copy DNA fragments spanning the region containing the HD gene will be analyzed to determine which represent portions of expressed genes and whether any detect DNA sequence rearrangements in patients with HD. Genomic and cDNA clones representing expressed genes in the vicinity of the HD gene will be examined to determine if their expression and/or structure is altered in patients with the disease. If such alterations are found, the candidate gene will be isolated from genomic DNA libraries from and HD patient and the structure and sequence compared to the corresponding gene from unaffected individuals. The isolation of the HD gene and an understanding of its function will provide the capability for 100% accurate preclinical diagnosis of this late age of onset disorder and may well lead to the development of effective therapies to prevent or delay onset of symptoms.