CONSEQUENCES OF EXPANDED CAG IN HUNTINGTON'S DISEASE

亨廷顿病(HD)基因缺陷的鉴定， 我们在过去的一段时间里完成的，已经移动了 对这种疾病的研究进入了一个新的令人兴奋的时代。立竿见影 已经感觉到了这一发现，因为CAG的测量 IT15中的三核苷酸长度提供了一种特异、可靠、直接的HD 可应用于有问题的病例或用于 症状前或产前诊断。更重要的是，这个发现 把我们放在了一条通往 扩展的CAG重复序列对选择性神经元丢失特征的影响 这是一种混乱。有希望的是，这个步骤的最终描述 路径将提供对HD发病机制的详细了解，并可能 针对特定过程开发合理的治疗方法 治疗这种毁灭性的疾病。我们打算开始这项工作 通过探索起源、行为和直接后果进行重要的跋涉 亨廷顿病基因中扩增的CAG重复序列。 我们将使用扩展的委内瑞拉高清系列，其中高清是 在数百个个体的单个单倍型上分离，以解决 关于HD CAG的可变性和行为的基本问题 在代代相传的过程中重复；2)确定 发生重复序列不稳定的精子发生阶段；3) 研究CAG扩张的后果，开发一组 免疫试剂描绘亨廷顿蛋白的基本特征， 尤其是确定CAG重复序列是否被翻译成 多聚谷氨酰胺；以及4)鉴定和表征编码蛋白质的基因 与普通或HD猎人蛋白相互作用。这些研究将 提供CAG重复行为的详细描述，并可 推测其在HD中不稳定的机制。他们还将提供一个 直接比较正常和HD亨廷顿蛋白，将揭示 突变作用于RNA或蛋白质水平。这些研究将 生成继续进行级联过程所需的知识和试剂 导致神经细胞死亡的事件。

The identification of the genetic defect causing Huntington's disease (HD), which we accomplished during the past period of this grant, has moved research in this disorder into a new and exciting era. An immediate impact of the discovery has already been felt, as the measurement of CAG trinucleotide length in IT15 has provided a specific, reliable, direct HD diagnostic test that can be applied to problematic cases or to presymptomatic or prenatal diagnosis. What is more important, the finding has placed us at the genetic starting point of a pathway that leads from the expanded CAG repeat to the selective neuronal loss characteristic of the disorder. Hopefully, the eventual delineation of the steps in this pathway will provide a detailed understanding of HD pathogenesis, and may target specific processes for the development of rational therapies for treating this devastating disorder. It is our intention to begin this important trek by exploring the origin, behavior and immediate consequences of the expanded CAG repeat in the Huntington's disease gene. We will 1) use the extended Venezuela HD pedigree, in which HD is segregating on a single haplotype in hundreds of individuals, to address fundamental questions concerning the variability and behavior of the HD CAG repeat as it is passed from generation to generation; 2) determine the stage of spermatogenesis at which instability of the repeat occurs; 3) investigate the consequences of CAG expansion by developing a battery of immunologic reagents to delineate the basic characteristics of huntingtin, particularly to determine whether the CAG repeat is translated into polyglutamine; and 4) identify and characterize genes encoding proteins that interact with either normal or HD huntingtin. These studies will provide a detailed description of the behavior of the CAG repeat and may implicate a mechanism for its instability in HD. They will also provide a direct comparison of normal and HD huntingtin that will reveal whether the mutation acts at the RNA or at athe protein level. These studies will generate the knowledge and reagents necessary to proceed along the cascade of events leading to neuronal cell death.