The Molecular Basis of Infantile Neuroaxonal Dystrophy

描述（由申请人提供）：本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，这是一种常染色体隐性遗传病，以进行性运动和感觉障碍为特征。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周围神经系统中广泛分布膨胀的轴突。有缺陷的逆行轴突运输是导致INAD表型的假设机制；然而，INAD的分子缺陷尚不清楚。通过确定这种致命的儿童疾病的一个或多个基因，我们可以提供诊断分子测试，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。我们已经建立了两种独特的资源，将加速人类和患有INAD的小鼠的疾病基因发现。首先，我们拥有世界上最大的来自INAD家族的表型数据和DNA样本，利用这些数据，我们利用连锁分析绘制了该疾病的主要基因（INAD1）。其次，我们建立了一个突变小鼠群体，这些小鼠患有早发性神经退行性疾病，病理变化与患有INAD的人类相同。这种散发性突变体已被杂交成一种遗传上不同的菌株，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认识。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致病突变的谱系；2)在小鼠INAD模型中鉴定疾病基因；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.