MOLECULAR BASIS OF LATE INFANTILE NCL

描述：(摘自摘要)这项研究的长期目标 是为了了解神经元蜡样脂褐素沉积症的分子基础 (NCL；巴顿病)。NCL是最常见的神经退行性变 儿童期精神障碍，以进行性精神障碍为特征 病情恶化、癫痫发作和视力丧失。这种疾病的特点 是超微结构中自体荧光脂类物质的堆积 神经元和其他细胞类型中的胞体。现在有五个主要的子类型 根据发病年龄、临床表现和 超微结构：婴儿型(含)，仅见于 芬兰人口；婴儿晚期(LNCL)；青少年(JNCL)；和成人 (库夫斯病)。除了可能的成体外， 遗传是常染色体隐性遗传。据估计，NCL的发病率为 1-5/10万。尽管进行了密集的努力，但人类体内的基本生化缺陷 NCL继续躲避研究人员。目前还没有有效的治疗方法 这种致命的疾病。 少年型(CLN3)、婴儿型(CLN1)和CLN5的基因座有 通过遗传连锁分析定位到染色体16p、1p和13q 分别进行了分析。晚期婴儿缺陷(CLN2)尚未被标测， 尽管具有紧密连锁标记的连锁分析将其排除在 16号染色体上的JNCL基因座和1号染色体上的INCL1基因座。 目前这项提议的第一个目标是使用遗传连锁方法 使用高度多态的标记来定位和细化地图位置 CLN2.此信息将用于实施位置 用于分离和后续鉴定的克隆策略 基因。在整个项目期间，候选基因将是 用生化和免疫组化方法评价它们在NCL发病机制中的作用 组织学研究和我们对候选JNCL基因的分析。 与紧密相连的高信息量侧翼的标识 标志物，基于DNA的产前和症状前诊断可以 在真正的克隆和克隆之前很久就提供给高危家庭 疾病基因的特征。突变的鉴定 基因内的基因将允许在选定的人群中进行携带者测试。 了解LNCL潜在的分子缺陷将有助于阐明 参与疾病发病机制的生化途径， 阐明了其他油脂类脂褐素病的可能原因，以及 为合理治疗的设计提供一个起点。

DESCRIPTION: (From Abstract) The long-term objective of this research is to understand the molecular basis of neuronal ceroid lipofuscinosis (NCL; Batten disease). NCL is the most common neurodegenerative disorder of childhood and is characterized by 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 cell types. Five major sub-types are now recognized on the basis of age-at-onset, clinical presentation, and ultrastructural morphology: infantile (INCL), found exclusively in the Finnish population; 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 loci for the juvenile (CLN3), infantile (CLN1) types, and CLN5 have been mapped by genetic linkage analysis to chromosome 16p, 1p, and 13q respectively. The late infantile defect (CLN2) has not yet been mapped, although linkage analysis with tightly linked markers excludes it from the JNCL locus on chromosome 16 and the INCL locus on chromosome 1. The first goal of this current proposal is to use genetic linkage methods with highly polymorphic markers to localize and refine the map position of the CLN2. This information will be used to implement a positional cloning strategy for the isolation and subsequent characterization of the gene. Throughout this project period, candidate genes will be evaluated for their role in the pathogenesis of NCL by biochemical and histological studies and by our analysis of candidate JNCL genes. 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 underlying LNCL 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.