The Molecular Basis of Infantile Neuroaxonal Dystrophy

描述（由申请人提供）：该项目的目标是确定婴儿神经轴索营养不良（INAD）的遗传基础，INAD是一种常染色体隐性遗传疾病，其特征是进行性运动和感觉障碍。这种形式的神经轴突营养不良的关键病理特征是在整个中枢和外周神经系统中广泛分布的膨胀轴突。逆向轴突运输缺陷是导致INAD表型的假设机制;然而，INAD中的分子缺陷仍然未知。通过鉴定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检测，并开始研究疾病的发病机制，作为开发合理治疗方法的一步。我们已经建立了两个独特的资源，这将加速人类和患有INAD的小鼠的疾病基因发现。首先，我们保持了全球最大的表型数据和DNA样本收集INAD家庭，我们已经映射了一个主要的基因（INAD 1），这种疾病使用连锁分析。其次，我们建立了一个突变小鼠群体，这些小鼠具有早发性神经退行性疾病和与INAD患者相同的病理变化。这种散发性突变体已经与遗传上不同的菌株杂交，以绘制和分离缺陷鼠基因。这些小鼠的研究将补充人类的研究，并扩展我们对神经轴索营养不良分子基础的认识。我们将利用这些资源来实现我们的特定目标：1）鉴定人类INAD 1基因并分析INAD家系中的致病突变; 2）鉴定INAD小鼠模型中的疾病基因; 3）启动INAD基因及其蛋白产物的结构和功能表征。

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.