Molecular Basis of the Demylinating Disorder ADLD

描述(研究者摘要)：常染色体显性遗传性脑白质营养不良(ADLD) 是一种罕见的成人起病的脱髓鞘障碍。我们已经确认了6个家庭 患上了这种疾病。其中两个是大血统，对他们来说 临床、神经放射学和神经病理学数据的数量已经 收好了。尽管这些患者与其他患者有许多共同的临床特征 白质障碍，独特的神经病理结果表明 这种疾病的发生既不存在于髓鞘结构缺陷 过氧化体中的蛋白质或脂肪酸代谢。ADLD也不是一种免疫 多发性硬化症(MS)等疾病。我们已经证明了ADLD中的病变 大脑的星形胶质细胞数量急剧减少，而幸存的 星形细胞在形态上非常异常。我们假设ADLD 由于缺陷干扰了髓鞘形成中的一种独特成分 这一过程和对这一缺陷的理解可能会为 髓鞘的维持和更新的过程。我们已经定位了基因 导致这两个大家族中的ADLD发生在染色体5q3 1上。精细定位 进一步缩小了区域和一个完整的物理图谱预测基因 居住在3兆数据库内，其中大部分已经被测序。侯选人 基因鉴定和检测正在进行中。该区域的一些基因具有 已经使用各种突变分析策略消除了。几个 目前正在对可能的候选者进行测试，其中包括一种新的基因 多个类EGF结构域。该提案概述了一项战略，以确定 并对该基因进行了表征。可用的患者材料、物理映射 试剂和基因组序列为我们实现这一目标做了很好的准备。在……里面 此外，将继续进行实验，以初步表征 野生型和突变型ADLD蛋白。了解这一现象的原因 脱髓鞘障碍可能会为调节髓鞘脱失的遗传因素提供线索 获得性脑白质营养不良的表现。最终，一种新元素的发现 在髓鞘的合成和维持中可能提供新的靶点 在更常见的疾病中，如MS，可能会刺激重新髓鞘形成的化合物。

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.