POSITIONAL CLONING STUDIES OF NARCOLEPSY GENES

描述 (根据申请人的描述改编)发作性睡病-猝倒是一种睡眠 影响美国0.05%总人口的疾病。这个 发作性睡病的发生涉及到特定的环境因素 遗传背景。环境因素的重要性可以是 25%-31%的同卵双胞胎在 文学作品与发作性睡病格格不入。易感基因之一 因子位于MHC DQ区域。百分之八十五到百分之百 患者共享一种特定的HLA等位基因，DQB1+0602，而普通患者的DQB1+0602为12%-38% 不同民族的人口。除人类白细胞抗原外的其他遗传因素 也有可能参与其中。即使真正的多人家庭很少见， 发作性睡病患者的一级亲属中有1-2%受到影响 被无序状态所困扰。这些调查人员发现了几个多用途的家庭 受影响成员众多，与人类白细胞抗原无明显的单倍型连锁。 使用犬科动物模型进行的研究也说明了这一点的重要性。 非MHC基因在疾病易感性中的作用。在这个模型中，嗜睡症是 以单个常染色体隐性性状(Canarc1)传递，与 MHC-II类基因多态性。CANARC-1的一个牢固的连锁标记 已识别(当前LOD分数在0%重组时为15.3)。 在这个项目中，将在两只犬身上使用定位克隆方法 和人类分离新的发作性睡病易感基因。四十八岁 伴有发作性睡病-猝倒和微卫星标记的多个家族 基因组扫描实验将用于确定人类基因组片段 含有发作性睡病易感基因。犬齿的一种大的嵌入物 (BAC)文库将首先构建。此资源将用于 构建基因组重叠群并开发新的多态标记 先前发现的犬发作性睡病基因标记物。到时候他们就会 犬类和人类多态的易感区域饱和 标记以缩小包含候选发作性睡病基因的区域。 候选基因随后将被分离并使用高通量进行测试 基因组测序和其他分子技术直到疾病 确定了易感基因。该组织认为，这种方法将 揭示发作性睡病的病因并开辟新的治疗途径 无序。

DESCRIPTION (Adapted from the applicant's description) Narcolepsy-cataplexy is a sleep disorder affecting 0.05% of the general population in the US. The development of narcolepsy involves environmental factors on a specific genetic background. The importance of environmental factors can be illustrated by the fact that 25-31% of monozygotic twins reported in the literature are discordant for narcolepsy. One of the predisposing genetic factors is located in the MHC DQ region. Eighty-five to 100 percent of all patients share a specific HLA allele, DQB1+0602 versus 12-38% of the general population in various ethnic groups. Genetic factors other than HLA are also likely to be involved. Even if genuine multiplex families are rare, 1-2% of the first degree relative of a patient with narcolepsy are affected by the disorder. These investigators have found a few multiplex families with numerous affected members and no apparent haplotype linkage with HLA. Studies using a canine model of the disorder also illustrate the importance of non MHC genes in disease predisposition. In this model, narcolepsy is transmitted as a single autosomal recessive trait (canarc-1) unlinked with MHC class II polymorphisms. A solid linkage marker for canarc-1 has been identified (current LOD score=15.3 at 0% recombination). In this project, a positional cloning approach will be used in both canines and humans to isolate novel narcolepsy susceptibility genes. Forty-eight multiplex families with narcolepsy-cataplexy and a microsatelite marker genome scanning experiment will be used to determine human genomic segments containing narcolepsy susceptibility genes. In canines, a large insert (BAC) library will first be constructed. This resource will be used to build genomic contigs and to develop new polymorphic markers around the previously identified canine narcolepsy gene marker. They will then saturate susceptibility regions in both canines and humans with polymorphic markers to narrow down the region containing candidate narcolepsy genes. Candidate genes will then be isolated and tested using high throughput genomic sequencing and other molecular techniques until disease susceptibility genes are identified. This group believes this approach will reveal the cause of narcolepsy and open new therapeutic avenues for the disorder.