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: 7105884
• 负责人: SUSAN J HAYFLICK
• 金额: $ 26.43万
• 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 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7105884
• 关键词: autosomal recessive trait; biological models; chemical stability; clinical research; disease /disorder etiology; disease /disorder model; family genetics; gene expression; gene mutation; genetic screening; hereditary motor and sensory neuropathy; human genetic material tag; human subject; laboratory mouse; linkage mapping; neurogenetics; patient oriented research; protein structure function

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：该项目的目标是确定婴儿神经轴突营养不良症（INAD）的遗传基础，这是一种以进行性运动和感觉障碍为特征的常染色体隐性遗传疾病。这种形式的神经轴突营养不良的关键病理特征是膨胀的轴突广泛分布在整个中枢和周围神经系统中。有缺陷的逆行轴突运输是导致 INAD 表型的一种假设机制；然而，INAD 的分子缺陷仍然未知。通过识别这种致命的儿童疾病的一个或多个基因，我们可以提供诊断性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，将加速人类和小鼠 INAD 疾病基因的发现。首先，我们维护着全球最大的 INAD 家族表型数据和 DNA 样本集合，并通过连锁分析绘制了该疾病的主要基因 (INAD1)。其次，我们建立了一群患有早发性神经退行性疾病和与人类 INAD 相同的病理变化的突变小鼠。这种散发性突变体已与遗传上不同的品系杂交，以便绘制和分离有缺陷的小鼠基因。对这些小鼠的研究将补充人类的研究，并扩展我们对神经轴突营养不良的分子基础的了解。我们将利用这些资源来实现我们的具体目标：1）鉴定人类INAD1基因并分析INAD谱系中的致病突变； 2) 鉴定INAD小鼠模型中的疾病基因； 3) 启动INAD基因及其蛋白质产物的结构和功能表征。