The Molecular Basis of Infantile Neuroaxonal Dystrophy

婴儿神经轴突营养不良的分子基础

• 批准号: 7348430
• 负责人: SUSAN J HAYFLICK
• 金额: $ 25.65万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-10 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7348430
• 关键词: Affect; Axon; Axonal Transport; Brain; Candidate Disease Gene; Childhood; Chromosomes; Chromosomes, Human, Pair 15; Clinical; Collection; Complement; DNA; Data; Defect; Diagnosis; Diagnostic tests; Disease; Family; Genes; Genetic; Goals; Health; Human; Human Chromosomes; Impairment; Individual; Investigation; Knowledge; Laboratories; Lead; Lod Score; Maps; Modeling; Molecular; Molecular Diagnostic Testing; Motor; Mus; Mutant Strains Mice; Mutate; Mutation; Mutation Analysis; Nature; Nerve; Neuroaxonal Dystrophies; Neurodegenerative Disorders; Orthologous Gene; Pathogenesis; Pathologic; Patients; Pattern; Peripheral Nervous System; Phenotype; Prenatal Diagnosis; Process; Proteins; Resources; Sampling; Screening procedure; Seitelberger' s Disease; Sensory; Spinal Cord; Synteny; Therapeutic; Translating; base; disease-causing mutation; early childhood; early onset; gene discovery; genetic linkage analysis; genetic pedigree; genome-wide linkage; human disease; mouse model; mutant

The goal of this project is to identify the genetic basis of infantile neuroaxonal dystrophy (INAD), an autosomal recessive disorder characterized by progressive motor and sensory impairment. The key pathologic feature of this form of neuroaxonal dystrophy is the widespread distribution of distended axons throughout the central and peripheral nervous systems. Defective retrograde axonal transport is a hypothesized mechanism leading to the INAD phenotype; however, the molecular defect in INAD remains unknown. By identifying a gene or genes for this fatal childhood disorder, we can offer diagnostic molecular testing and begin to investigate disease pathogenesis as a step towards developing rational therapeutics. We have established two unique resources that will accelerate disease gene discovery in humans and mice with INAD. First, we maintain the largest worldwide collection of phenotype data and DNA samples from INAD families, with which we have mapped a major gene (INAD1) for this disorder using linkage analysis. Second, we have established a colony of mutant mice with early-onset neurodegenerative disease and pathologic changes identical to those seen in humans with INAD. This sporadic mutant has been crossed to a genetically distinct strain in order to map and isolate the defective murine gene. Studies in these mice will complement those in humans and extend our knowledge of the molecular basis of the neuroaxonal dystrophies. We will use these resources to achieve our specific aims to: 1) identify the human INAD1 gene and analyze INAD pedigrees for disease-causing mutations; 2) identify the disease gene in a mouse model of INAD; and 3) initiate structural and functional characterization of the INAD genes and their protein products.

该项目的目标是确定婴儿神经轴突营养不良 (INAD) 的遗传基础，这是一种 常染色体隐性遗传病，其特征是进行性运动和感觉障碍。关键 这种形式的神经轴突营养不良的病理特征是广泛分布的扩张轴突 遍及中枢和周围神经系统。逆行轴突运输缺陷是 导致 INAD 表型的假设机制；然而，INAD 的分子缺陷仍然存在 未知。通过识别这种致命的儿童疾病的一个或多个基因，我们可以提供诊断分子 测试并开始研究疾病发病机制，作为开发合理疗法的一步。 我们建立了两种独特的资源，将加速人类疾病基因的发现 和患有INAD的小鼠。首先，我们拥有全球最大的表型数据和 DNA 样本集合 来自 INAD 家族，我们利用连锁绘制了这种疾病的主要基因 (INAD1) 分析。其次，我们建立了一群患有早发性神经退行性疾病的突变小鼠 和病理变化与患有 INAD 的人类相同。这种零星的突变体已被 与遗传上不同的品系杂交，以绘制和分离有缺陷的小鼠基因。研究这些 小鼠将补充人类的缺陷，并扩展我们对神经轴突分子基础的了解 营养不良。我们将利用这些资源来实现我们的具体目标：1) 识别人类 INAD1 基因 并分析 INAD 谱系中的致病突变； 2) 鉴定小鼠模型中的疾病基因 伊纳德； 3) 启动INAD基因及其蛋白质产物的结构和功能表征。