MOLECULAR STUDIES OF DOMINANT AUTOSOMAL SPASTIC PARAPLEGIA (SPG)

显性常染色体痉挛性截瘫 (SPG) 的分子研究

• 批准号: 6444653
• 负责人: Douglas A. Marchuk
• 金额: $ 20.73万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6444653
• 关键词: artificial chromosomes; autosomal dominant trait; chromosomes; clinical research; cytogenetics; data collection; family genetics; gene mutation; genetic library; genetic mapping; genetic screening; genotype; human data; human genetic material tag; human subject; molecular cloning; molecular pathology; neurogenetics; nucleic acid repetitive sequence; nucleic acid sequence; paraplegia; phenotype; polymerase chain reaction; spastic paralysis

Hereditary Spastic Paraplegia (SPG; OMIM 182600) comprises a group of neurodegenerative disorders characterized by progressive spasticity of the lower limbs. SPG has been classified into pure (uncomplicated) and complex (complicated) forms based on clinical symptoms; patients with complicated SPG exhibit in addition to spasticity of the lower limbs other neurological symptoms, such as mental retardation, retinal changes, peripheral neuropathy, and ataxia. Decreasing age of onset and/or increasing severity in successive generations has also been noted, suggesting anticipation of SPG symptoms. SPG is genetically heterogeneous; autosomal dominant "uncomplicated" SPG families show locus heterogeneity, with linkage reported to chromosomes 2p (SPG4), 14q (SPG4), 14q (SPG3), and thus far a single kindred mapping to 15q (SPG6). A number of studies including our own suggest that the majority of most families are linked to chromosome 2p. In addition, anticipation has been reported for the chromosome 2 locus. Families unlinked to any of the three known loci have also been reported, suggesting that at least one additional major SPG locus. The minimum candidate regions (MCR) reported for SPG4 and SPG3 are a 3 cM interval between D2S352 and D2S367 and a 7 cM interval between D14S288 and D12S281, respectively. The purpose of this project is to continue our longstanding genetic analysis of autosomal dominant SPG. We will prioritize these studies by first attempting to positionally clone the SPG4 locus on chromosome 2p. Once identified we will carry out mutation analysis and phenotype/genotype correlations in conjunction with Cores B and C. Positionally cloning of additional SPG will commence upon successful completion of our chromosome 2 work. In addition, we propose to identify in conjunction with Core C other loci using our unlinked families.

遗传性痉挛性截瘫（SPG； OMIM 182600）包括一组神经退行性疾病，其特征是下肢进行性痉挛。 SPG已根据临床症状分为纯净（简单）和复杂（复杂）形式；复杂的SPG患者除了下肢痉挛外还表现出其他神经系统症状，例如智力低下，视网膜变化，周围神经病和共济失调。 还注意到了连续一代的发病年龄和/或日益严重程度的增加，这表明预期SPG症状。 SPG在遗传上是异质的。常染色体显性“简单” SPG家族表现出基因座异质性，并报告了连接染色体2P（SPG4），14q（SPG4），14q（SPG3），迄今为止，单个类似的映射到15q（SPG6）。许多研究包括我们自己的研究表明，大多数家庭中的大多数与2p染色体有关。此外，还报道了对2号染色体基因座的预期。还报道了与三个已知基因座中的任何一个链接的家庭，这表明至少有一个主要的SPG基因座。 SPG4和SPG3报告的最小候选区域（MCR）分别在D2S352和D2S367之间的3 cm间隔和D14S288和D12S281之间的7 cm间隔。该项目的目的是继续我们对常染色体显性SPG的长期遗传分析。我们将首先尝试将SPG4基因座定位在2p染色体上，从而优先考虑这些研究。一旦确定，我们将与核心B和C结合进行突变分析和表型/基因型相关性。在成功完成我们的2染色体工作时，将开始额外SPG的定位克隆。此外，我们建议使用我们的未链接家庭与Core C其他基因座结合确定。