TRINUCLEOTIDE REPEATS AND NEUROLOGIC DISEASE

三核苷酸重复与神经系统疾病

• 批准号: 6736221
• 负责人: RUSSELL L MARGOLIS
• 金额: $ 36.79万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-15 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6736221
• 关键词: Huntington' s disease; Parkinson' s disease; cerebellar ataxia /dyskinesia; clinical research; degenerative motor system disease; gene expression; gene mutation; genetic mapping; human subject; information dissemination; neural degeneration; nucleic acid repetitive sequence; open reading frames; polymerase chain reaction

DESCRIPTION: (Adapted from investigator's abstract): Ten neurodegenerative diseases (Huntington's disease; spinocerebellar ataxia (SCA) types 1, 2, 3, 6, 7, 8 and 12; dentatorubral-pallidoluysian atrophy; and spinal and bulbar muscular atrophy) are now known to be caused by expansions of CAG/CTG trinucleotide repeats. The P.I. hypothesizes that similar disorders, including other forms of spinocerebellar ataxia, familial spastic paraplegia, and some types of familial Parkinsonism, may also be caused by expansions of CAG/CTG repeats. He proposes a three-part plan to test this hypothesis. First, the P.I. will search the genomes of subjects with progressive neurodegenerative disorders of unknown etiology with an assay (known as repeat expansion detection, or RED) that enables identification of long CAG/CTG repeat expansions. Expansions detected by this method will be cloned, along with flanking sequence, and they will develop PCR-based assays to search for the expansions in other subjects. Secondly, they will develop a catalogue of CAG/CTG repeats in the human genome. This will be accomplished by systematic searches of the genetic data banks, supplemented by cloning efforts in the P.I.'s laboratory in collaboration with Life Technologies, Inc. They will determine the reading frame (if any) of each repeat, localize each repeat to a chromosomal locus, develop a PCR assay for testing the length of each repeat, and place this information on a publicly accessible Web site. The P.I. and an extensive group of collaborators will use these assays to test for expansions of specific repeats in subjects and controls. Third, the P.I. will undertake preliminary mechanistic studies of novel expansion mutations, including determination of whether the expansion is transcribed and translated and the effect of the expansion on gene expression. Overall, the proposed experiments will enable a systematic test for CAG/CTG expansion mutations in a variety of devastating neurodegenerative diseases.

描述：（改编自研究者的摘要）：十种神经退行性疾病 疾病（亨廷顿病；脊髓小脑性共济失调 (SCA) 1、2、3、6 型， 7、8 和 12；齿状红核-苍白球路易体萎缩;以及脊柱和延髓 肌肉萎缩）现在已知是由 CAG/CTG 扩张引起的 三核苷酸重复。 P.I.假设类似的疾病，包括 其他形式的脊髓小脑共济失调、家族性痉挛性截瘫和一些 家族性帕金森病的类型，也可能是由 CAG/CTG 的扩展引起的 重复。他提出了一个由三部分组成的计划来检验这一假设。首先，P.I. 将搜索患有进行性神经退行性疾病的受试者的基因组 通过测定（称为重复扩增 检测，或 RED），能够识别长 CAG/CTG 重复 扩展。通过此方法检测到的扩展将被克隆，同时 侧翼序列，他们将开发基于 PCR 的检测方法来寻找 其他科目的拓展。其次，他们将制定一个目录 CAG/CTG 在人类基因组中重复。这将通过系统地完成 基因数据库的搜索，并辅以克隆工作 P.I. 的实验室与 Life Technologies, Inc. 合作。他们将 确定每个重复的阅读框（如果有），将每个重复定位到 染色体位点，开发 PCR 检测方法来测试每个重复的长度， 并将此信息放在可公开访问的网站上。 P.I.和一个 广泛的合作者群体将使用这些分析来测试扩展 受试者和对照中的特定重复。第三，P.I.将承担 新扩展突变的初步机制研究，包​​括 确定扩展是否被转录和翻译以及 扩增对基因表达的影响。总体而言，建议的实验 将能够对多种细胞中的 CAG/CTG 扩增突变进行系统测试 毁灭性的神经退行性疾病。

项目成果

Neuropathology and Cellular Pathogenesis of Spinocerebellar Ataxia Type 12.

12 型脊髓小脑共济失调的神经病理学和细胞发病机制。

• DOI: 10.1002/mds.26348
• 发表时间: 2015
• 期刊: Movement disorders : official journal of the Movement Disorder Society
• 作者: O'Hearn,ElizabethE;Hwang,HyonS;Holmes,SusanE;Rudnicki,DobrilaD;Chung,DanielW;Seixas,AnaI;Cohen,RachaelL;Ross,ChristopherA;Trojanowski,JohnQ;Pletnikova,Olga;Troncoso,JuanC;Margolis,RussellL
• 通讯作者: Margolis,RussellL

Clinical signs and symptoms in a large hereditary spastic paraparesis pedigree with a novel spastin mutation.

具有新型 spastin 突变的大型遗传性痉挛性截瘫家系的临床体征和症状。

• DOI: 10.1002/mds.20077
• 发表时间: 2004
• 期刊: Movement disorders : official journal of the Movement Disorder Society
• 作者: Nicholas,AnthonyP;O'Hearn,Elizabeth;Holmes,SusanE;Chen,Dung-Tsa;Margolis,RussellL
• 通讯作者: Margolis,RussellL