CONSEQUENCES OF EXPANDED CAG IN HUNTINGTON'S DISEASE

导致亨廷顿病（HD）的遗传缺陷的鉴定， 在过去的一段时间里，我们完成了这项赠款， 将这种疾病的研究带入了一个令人兴奋的新时代 立竿见影的影响 这一发现的重要性已经被感受到，因为CAG的测量 IT 15中的三核苷酸长度提供了一种特异、可靠、直接的HD 诊断测试，可以应用于有问题的情况下，或 症状前或产前诊断。 更重要的是， 使我们处于一条基因路径的起点， 扩增的CAG重复序列对选择性神经元丢失的特征是 紊乱 希望，最终的步骤描述， 通路将提供对HD发病机制的详细了解， 针对特定的过程，以开发合理的治疗方法， 治疗这种毁灭性的疾病 我们打算开始这件事 通过探索起源，行为和直接后果， 在亨廷顿氏病基因中CAG重复序列的扩增。 我们将1）使用扩展的委内瑞拉HD谱系，其中HD是 在数百个个体中分离单个单倍型，以解决 关于HD CAG的变异性和行为的基本问题 重复，因为它是通过从一代到一代; 2）确定 精子发生阶段，重复序列不稳定; 3） 研究CAG扩张的后果，通过开发一系列 描述亨廷顿蛋白基本特征的免疫试剂， 特别是为了确定CAG重复是否被翻译成 多聚谷氨酰胺;和4）鉴定和表征编码蛋白质的基因 与正常或HD亨廷顿蛋白相互作用。 这些研究将 提供CAG重复的行为的详细描述，并且可以 暗示其在HD中不稳定机制。 他们还将提供一个 直接比较正常和HD亨廷顿蛋白， 突变作用于RNA或mRNA蛋白水平。 这些研究将 产生沿着级联进行所需的知识和试剂 导致神经元细胞死亡的事件。

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.