Molecular Basis of the Demylinating Disorder ADLD

描述（研究者摘要）：常染色体显性脑白质营养不良（ADLD） 是一种罕见的成人型脱髓鞘疾病我们已经确定了6个家庭 这种紊乱。其中两个是大谱系， 大量的临床、神经放射学和神经病理学数据已被 收集。尽管这些患者与其他患者有许多共同的临床特征， 白色物质障碍，独特的神经病理学结果表明， 这种疾病的发生既不在于结构髓鞘的缺陷， 过氧化物酶体中的蛋白质或脂肪酸代谢。ADLD不是免疫系统 多发性硬化症（MS）。我们已经证明了ADLD中的病变 大脑中星形胶质细胞的数量急剧减少， 星形胶质细胞在形态上非常异常。我们假设ADLD 是由于髓鞘形成中的一个独特元素受到干扰 这一过程和理解这一缺陷可能会提供新的见解， 髓鞘的维持和更新过程。我们已经定位了 导致这两个大家族的ADLD均发生在染色体5q31上。精细映射具有 进一步缩小了该区域，一个完整的物理图谱预测该基因， 存在于3兆碱基范围内，其中大部分已经被测序。候选 基因鉴定和测试正在进行中。该地区的一些基因 已经被各种突变分析策略消除了。几 目前正在测试可能的候选者，包括一种新的基因， 多个EGF样结构域。该提案概述了一项战略， 并表征该基因。可用患者材料，物理标测 试剂和基因组序列使我们能够很好地实现这一目标。在 此外，将进行实验，以初步表征 野生型和突变型ADLD蛋白。了解这一原因 脱髓鞘疾病可能会产生遗传因素的线索，调节 获得性脑白质营养不良的表达。最终发现了一种新元素 在髓鞘的合成和维持中的作用可能提供了一个新的靶点， 在更常见的疾病如MS中可能刺激髓鞘再生的化合物。

DESCRIPTION (Investigator's abstract): Autosomal dominant leukodystrophy (ADLD) is a rare adult-onset demyelinating disorder. We have identified 6 families with this disorder. Two of these are large pedigrees for whom a tremendous amount of clinical, neuroradiological and neuropathological data has been collected. Although these patients share many clinical features with other white matter disorders, unique neuropathological findings suggest that the genesis of this disorder neither resides in defects of structural myelin proteins nor fatty acid metabolism in peroxisomes. ADLD is not an immune disease like multiple sclerosis (MS). We've demonstrated that lesions in ADLD brain have dramatic reduction in astrocyte number and that the surviving astrocytic cells are morphologically very abnormal. We hypothesize that ADLD results from a defect that interferes with a unique element in the myelination process and that understanding of this defect may provide novel insights into the process of myelin maintenance and turnover. We have localized the gene causing ADLD in these two large families to chromosome 5q3 1. Fine mapping has further narrowed the region and a complete physical map predicts the gene to reside within 3 megabases, much of which has already been sequenced. Candidate gene identification and testing are underway. Some genes in the region have already been eliminated using various mutation analysis strategies. Several plausible candidates are currently being tested including a novel gene with multiple EGF-like domains. This proposal outlines a strategy for identifying and characterizing the gene. Available patient material, physical mapping reagents and genomic sequence position us well for accomplishing this goal. In addition, experiments will be pursued toward preliminary characterization of both the wild-type and mutant ADLD protein. Understanding the cause of this demyelinating disorder may yield clues to genetic factors that modulate the expression of acquired leukodystrophies. Ultimately, discovery of a new element in the synthesis and maintenance of myelin may provide a novel target for compounds that may stimulate remyelination in more common disorders like MS.