Novel genetic determinants of the neuromuscular SMA phenotype

神经肌肉 SMA 表型的新遗传决定因素

• 批准号: 8468220
• 负责人: Umrao Monani
• 金额: $ 33.78万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8468220
• 关键词: Affect; Animal Model; Animals; Backcrossings; Biochemical Pathway; Biology; Cataloging; Catalogs; Cells; Collection; Congenic Strain; Databases; Defect; Disease; Ensure; Exhibits; Functional disorder; Funding; Future; Generations; Genes; Genetic; Genetic Determinism; Genome; Genomics; Goals; Health; Homologous Gene; Human; Individual; Lead; Learning; Light; Link; Maps; Modification; Molecular; Molecular Target; Motor; Motor Neurons; Mouse Strains; Mus; Mutant Strains Mice; Mutation; Natural History; Nerve Degeneration; Neuromuscular Diseases; Outcome; Palliative Care; Pathology; Pathway interactions; Patients; Phenotype; Physiological; Polymorphic Microsatellite Marker; Process; Program Development; Proteins; RNA Splicing; Reporting; Research; Research Personnel; Residual state; Resort; SMN2 gene; Sequence Analysis; Severity of illness; Siblings; Site; Spinal Muscular Atrophy; Testing; Transgenes; Transgenic Mice; United States National Institutes of Health; base; comparative; congenic; design; disease phenotype; effective therapy; genetic strain; human disease; interest; mouse model; mutant; neuromuscular; neuromuscular system; novel; pre-clinical; protein function; research study; snRNP Biogenesis; tool

DESCRIPTION (provided by applicant): Spinal muscular atrophy (SMA) is a common, frequently fatal, autosomal recessive disorder caused by homozygous mutations in the Survival of Motor Neuron 1 (SMN1) gene that lead to a deficiency of the SMN protein. Residual protein is expressed from SMN2, a partially functional homologue of the SMN1 gene. There is presently no cure for SMA. Currently available treatments are palliative at best. Although much has been learned about the pathology and natural history of the human disease and notwithstanding proof-of-concept studies demonstrating rescue of an SMA phenotype by restoring SMN to mouse models of the disease, the biochemical pathway(s) linking low levels of the protein to neurodegeneration remain(s) obscure. The single established function of SMN in orchestrating snRNP biogenesis has failed to shed adequate light on the motor neuron phenotype observed in SMA, prompting the search for additional functions of the protein and/or genes linking SMN paucity and disrupted snRNP biogenesis to neuromuscular disease. Increasing SMN2 copy number leads to higher levels of the SMN protein in patients and mutant mice and results in milder phenotypes. However, in rare instances the correlation between SMN2 copies and disease severity no longer holds, implying the existence of additional genetic modifiers of the SMA phenotype. Identifying such modifiers is one way to uncover new, disease-relevant functions of the SMN protein or reveal effector genes through which a disruption in snRNP biogenesis causes the SMA phenotype. In this application for funding to the NIH, we have outlined experiments in two related aims to exploit a modification of the disease phenotype in mouse models of SMA to map and identify modifying loci. In aim 1 congenic strains of SMA mice will be created to precisely define how different genetic backgrounds affect the mutant phenotype. Additionally, mutants from defined inter-strain crosses between the congenic SMA carriers will be generated and characterized by molecular, cellular and phenotypic means. In aim 2, mutants with the most distinct disease phenotypes will be used in linkage studies to map and eventually identify modifier loci. To confirm the disease modifying effects of the identified loci we will re-introduce them into SMA mice exhibiting a "typical" disease phenotype. Our studies will have two important outcomes. First, they will uncover novel, disease-relevant biochemical pathways and thus inform the underlying biology of spinal muscular atrophy. Second, they will identify genes that could serve as new molecular targets for future SMA therapies. The results of our experiments will constitute an important step toward the design of safe and effective treatments for SMA patients.

描述（由申请人提供）：脊髓性肌萎缩症 (SMA) 是一种常见的、常常致命的常染色体隐性遗传疾病，由运动神经元存活 1 (SMN1) 基因的纯合突变导致 SMN 蛋白缺乏。残余蛋白由 SMN2 表达，SMN2 是 SMN1 基因的部分功能同源物。目前 SMA 尚无治愈方法。目前可用的治疗充其量只是姑息治疗。尽管人们对人类疾病的病理学和自然史有了很多了解，并且概念验证研究证明通过将 SMN 恢复到该疾病的小鼠模型中可以挽救 SMA 表型，但将低水平的蛋白质与神经退行性疾病联系起来的生化途径仍然不清楚。 SMN 在协调 snRNP 生物发生中的单一既定功能未能充分阐明 SMA 中观察到的运动神经元表型，促使人们寻找将 SMN 缺乏和 snRNP 生物发生破坏与神经肌肉疾病联系起来的蛋白质和/或基因的其他功能。增加 SMN2 拷贝数会导致患者和突变小鼠的 SMN 蛋白水平升高，并导致较温和的表型。然而，在极少数情况下，SMN2 拷贝数与疾病严重程度之间的相关性不再成立，这意味着 SMA 表型的其他遗传修饰剂的存在。识别此类修饰因子是揭示 SMN 蛋白新的、与疾病相关的功能或揭示效应基因的一种方法，通过这些效应基因，snRNP 生物发生的破坏会导致 SMA 表型。在这份向 NIH 提供资金的申请中，我们概述了两个相关目标的实验，即利用 SMA 小鼠模型中疾病表型的修饰来绘制和识别修饰位点。目标 1 将创建 SMA 小鼠同源品系，以精确定义不同遗传背景如何影响突变表型。此外，将产生来自同源 SMA 携带者之间确定的品系间杂交的突变体，并通过分子、细胞和表型手段进行表征。在目标 2 中，具有最独特疾病表型的突变体将用于连锁研究，以绘制并最终识别修饰位点。为了确认所识别基因座的疾病调节作用，我们将把它们重新引入表现出“典型”疾病表型的 SMA 小鼠中。我们的研究将有两个重要成果。首先，他们将发现新的、与疾病相关的生化途径，从而为脊髓性肌萎缩症的潜在生物学提供信息。其次，他们将确定可以作为未来 SMA 疗法新分子靶标的基因。我们的实验结果将成为设计 SMA 患者安全有效治疗方法的重要一步。