The Molecular Basis of Infantile Neuroaxonal Dystrophy

婴儿神经轴突营养不良的分子基础

基本信息

批准号：
7231385
负责人：
SUSAN J HAYFLICK
金额：
$ 26.14万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
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/7231385
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&apos 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

项目摘要

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）：该项目的目的是确定婴儿神经乳律营养不良的遗传基础（INAD），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障碍。这种形式的神经间质性营养不良的关键病理特征是整个中央和周围神经系统中扩张轴突的广泛分布。有缺陷的逆行轴突转运是导致INAD表型的假设机制。但是，INAD中的分子缺陷仍然未知。通过鉴定这种致命儿童疾病的基因或基因，我们可以提供诊断性分子测试，并开始研究疾病发病机理，这是发展理性治疗剂的一步。我们已经建立了两个独特的资源，这些资源将加速与INAD的人类和小鼠的疾病基因发现。首先，我们使用INAD家族的全球表型数据和DNA样本收集，使用链接分析，我们已经绘制了该疾病的主要基因（INAD1）。其次，我们已经建立了一种突变小鼠的菌落，具有早期发作的神经退行性疾病和病理变化，与INAD人类中的菌落相同。为了绘制和分离有缺陷的鼠基因，该散发突变体已被跨入遗传上不同的菌株。在这些小鼠中的研究将补充人类中的研究，并扩展我们对神经间质营养不良的分子基础的了解。我们将使用这些资源来实现我们的具体目标：1）确定人类INAD1基因，并分析因疾病引起疾病的突变的INAD谱系； 2）在INAD小鼠模型中鉴定疾病基因； 3）启动INAD基因及其蛋白质产物的结构和功能表征。