MOLECULAR BASIS OF JUVENILE NCL

这项研究的长期目标是了解分子 神经性蜡样脂褐素增多症(NCL；巴顿病)的基础。NCL 是儿童时期最常见的神经退行性疾病， 以进行性精神恶化、癫痫发作和视力为特征 损失。这种疾病的特点是自身荧光的积聚。 神经元和其他组织中超微结构胞体中的脂类物质。 现在根据发病年龄识别出四个主要亚型， 临床表现和超微结构形态：婴儿(包括)， 仅见于芬兰；婴儿晚期(LNCL)；青少年(JNCL)；以及 成人(库夫斯病)。除了可能的成体外， 遗传是常染色体隐性遗传。估计NCL的发病率 在1-5/10万之间。尽管进行了密集的努力，但基本的生化缺陷 在NCL中，研究人员仍然躲避着。没有有效的治疗方法 这一致命的疾病。 这项建议的具体目的是克隆和鉴定该基因 NCL的幼体，CLN3。CLN3现已由Genetic定位 与信息量大的微卫星标记连锁到16p12.1。它 建议通过更广泛的链接来完善CLN3的本地化 分析并通过定向克隆分离跨越该基因座的DNA。 这些克隆将用于精细结构、遗传和物理 作图，用于亚显微筛选受影响个体的面板 删除和重新安排以及确定候选人的身份 通过外显子捕获获得基因。 与紧密相连的高信息量侧翼的标识 可以提供标志物、基于DNA的产前和症状前诊断 在真正的克隆和特征描述之前很久就给了高危家庭 疾病基因的基因。基因内突变的鉴定 将允许在选定的人群中进行携带者测试。了解以下内容 JNCL的分子缺陷将有助于阐明生化途径 参与了这种疾病的发病机制，揭示了可能的 其他蜡样脂褐素增多的原因，并提供了一个起点 用于设计合理的治疗方法。

The long-term objective of this research is to understand the molecular basis of the neuronal ceroid lipofuscinoses (NCL; Batten Disease). NCL is the most common neurodegenerative disorder of childhood and is characterized the progressive mental deterioration, seizures, and vision loss. The hallmark of the disease is the accumulation of autofluorescent lipopigments in ultrastructural cytosomes in neurons and other tissues. Four major subtypes are now recognized on the basis of age of onset, clinical presentation, and ultrastructural morphology: infantile (INCL), found exclusively in Finland; late infantile (LNCL); juvenile (JNCL); and adult (Kufs disease). With the possible exception of the adult form, inheritance is autosomal recessive. The incidence of NCL is estimated at 1-5/100,000. Despite intensive effort, the basic biochemical defect in NCL continues to elude researchers. There is no effective treatment for this fatal disease. The specific aim of this proposal is clone and characterize the gene for the juvenile form of NCL, CLN3. CLN3 has now been localized by genetic linkage with highly informative microsatellite markers to 16p12.1. It is proposed to refine the localization of CLN3 by more extensive linkage analysis and to isolate the DNA spanning this locus by directed cloning. These clones will be used for fine structure genetic and physical mapping, for screening panels of affected individuals for sub-microscopic deletions and rearrangements, and for the identification of candidate genes by exon trapping. With the identification of closely-linked highly informative flanking markers, DNA-based pre-natal and pre-symptomatic diagnosis can be offered to at-risk families well before the actual cloning and characterization of the disease gene. The identification of mutations within the gene will allow carrier testing in selected populations. Knowledge of the molecular defect in JNCL will help elucidate the biochemical pathways involved in the pathogenesis of the disease, shed light on the possible cause of the other ceroid lipofuscinoses, and provide a starting point for the design of rational therapies.