MOLECULAR BASIS OF JUVENILE NCL

这项研究的长期目标是了解 神经元蜡样脂褐质沉积症（NCL; Batten病）的基础。 NCL 是儿童期最常见的神经退行性疾病， 特征是进行性精神衰退，癫痫发作， 损失 这种疾病的标志是自体荧光的积累 在神经元和其他组织的超微结构细胞质中的脂色素。 根据发病年龄，目前已确认四种主要亚型， 临床表现和超微结构形态学：婴儿（INCL）， 仅在芬兰发现;晚期婴儿（LNCL）;青少年（JNCL）;和 （Kufs病）。 可能除了成年人， 遗传是常染色体隐性遗传。 估计NCL的发生率 10万分之1-5 尽管付出了巨大的努力，但基本的生化缺陷 NCL的研究人员仍然没有找到答案。 尚无有效的治疗方法 这种致命的疾病。 该提案的具体目的是克隆和表征基因， NCL的幼年型，CLN 3。 CLN 3现已通过基因定位 与16p12.1高度信息微卫星标记连锁。 它 提出通过更广泛的连接来改进CLN 3的定位 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 映射，用于筛选受影响个体的亚显微镜 删除和重新安排以及确定候选人 exon trapping基因 随着紧密连锁的高信息侧翼的鉴定 可以提供基于DNA的产前和症状前诊断 在实际克隆和鉴定之前， 疾病的基因。 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。 知识 JNCL中的分子缺陷将有助于阐明生物化学途径 参与疾病的发病机制，揭示了可能的 其他蜡样脂褐质病的原因，并提供一个起点 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.