Molecular And Genetic Analysis Of Autosomal Dominant Spastic Paraplegia

描述(申请人提供)：遗传性痉挛截瘫(HSP)是一组神经退行性疾病，以进行性肢体痉挛为特征，与肌萎缩侧索硬化症(ALS)、遗传性运动神经病和轴索神经病具有引人入胜的临床和病理生理重叠。HSP具有常染色体显性、常染色体隐性和X连锁的遗传异质性。在已报道的30个HSP染色体基因座中，只有14个基因被确定。额外的HSP基因的鉴定和分子特征是提高我们对潜在的病理生理学的理解的关键。因此，我们将努力确定染色体19q(SPG12)上明确定义的HSP基因座的潜在基因。我们将通过与法国(Alexandra Durr博士)、意大利(Antonio Orlacchio博士)和英国(Evan Reid博士)的研究人员合作，获得所有已知的SPG12家族的DNA样本。已确定的SPG12基因将被包括在我们的突变筛选和功能研究中。我们成功的HSP遗传计划的不可或缺的基础是收集了超过15年的HSP家族。这个项目最近与主要调查人员一起被转移到迈阿密大学。该标本的扩大和临床改进是我们进行遗传和分子水平上的过敏性紫杉醇研究的基础。最近，我们已经确定了SPG31基因座的潜在基因，受体表达增强蛋白1(REEP1)，它似乎占所有HSP患者的6.5%，使其成为仅次于spastin和atlastin的第三大常见HSP基因。我们将对REEP1家族进行更详细的临床研究，并在安特卫普大学De Jonghe博士收集的370例HSP患者样本中筛选额外的REEP1突变。最后，我们提出了在新的线粒体蛋白REEP1中以及可能在SPG12基因中发现的突变的分子特征。莫赖斯博士是世界著名的线粒体疾病机制专家，也是这项拨款的新研究员，专门致力于解决第三个目标。我们坚信，只有这样一种综合的方法--临床、遗传和分子/功能--才能在理解过敏性紫杉醇方面取得重大进展。

DESCRIPTION (provided by applicant): Hereditary Spastic Paraplegia (HSP) comprises a group of neurodegenerative disorders characterized by progressive spasticity of the lower limbs and has fascinating clinical and pathophysiological overlap with amyotrophic lateral sclerosis (ALS), hereditary motor neuropathies, and axonal neuropathies. HSP is genetically heterogeneous with autosomal dominant, autosomal recessive, and X-linked forms. Genes have been identified for only 14 of the 30 reported HSP chromosomal loci. The identification and molecular characterization of additional HSP genes is key to improve our understanding of the underlying pathophysiology. Thus, we will strive to identify the underlying gene of the well-defined HSP locus on chromosome 19q (SPG12). We will have access to DNA samples from all known linked SPG12 families through collaborations with investigators in France (Dr Alexandra Durr), Italy (Dr. Antonio Orlacchio), and the UK (Dr. Evan Reid). An identified SPG12 gene will be included in our mutation screening and functional studies. The indispensable basis of our successful HSP genetic program has been the collection of HSP families over more than 15 years. This program has recently been moved with the principal investigators to the University of Miami. The expansion and clinical improvement of this collection is the basis of our genetic and molecular HSP research. Recently we have identified the underlying gene for the SPG31 locus, receptor expression enhancing protein 1 (REEP1), which appears to represent 6.5% of all HSP patients making it the third most common HSP gene after spastin and atlastin. We will clinically study the REEP1 families in more detail and screen for additional REEP1 mutations in a sample of 370 HSP patients collected by Dr. de Jonghe, University of Antwerp. Finally, we propose the molecular characterization of the mutations identified in the novel mitochondrial protein REEP1 and possibly in the SPG12 gene. Dr. Moraes is a world-renowned specialist for mitochondrial disease mechanisms and is a new investigator on this grant specifically to address the third aim. We strongly believe that only such an integrated approach - clinical, genetic, and molecular/functional - will yield significant progress in the understanding of HSP.