Molecular Genetics of Kleine-Levin Syndrome

克莱恩-莱文综合征的分子遗传学

• 批准号: 7628459
• 负责人: Emmanuel J Mignot
• 金额: $ 36.28万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7628459
• 关键词: Accounting; Adolescence; Affect; Alleles; Ashkenazim; Behavior; Behavioral; Candidate Disease Gene; Case Series; Case Study; Child; Childhood; Classification; Clinical; Collaborations; Computer Simulation; Country; DNA; Data; Desire for food; Development; Disease; Environmental Risk Factor; Europe; Family; Founder Effect; Functional disorder; Genes; Genetic; Genetic Predisposition to Disease; Goals; Human; Hyperphagia; Impaired cognition; Israel; Kleine-Levin Syndrome; Lead; Literature; Maps; Molecular Genetics; Mutation; Nature; Neuraxis; Orphan; Parents; Patients; Play; Population; Predisposition; Prevalence; Principal Investigator; Publishing; Questionnaires; Rare Diseases; Recruitment Activity; Reporting; Research; Research Personnel; Sampling; Scanning; Single Nucleotide Polymorphism; Sleep; Susceptibility Gene; United States; Variant; base; density; effective therapy; follow-up; follower of religion Jewish; genetic analysis; genome wide association study; insight; neuropsychiatry; novel; proband; programs; sleep regulation

DESCRIPTION (provided by applicant): Kleine-Levin Syndrome (KLS) is an orphan neuropsychiatric disorder, typically starting in childhood or adolescence. Its primary manifestation is a periodic hypersomnia (dramatic increases in sleep amounts) of central nervous system origin. These bouts of hypersomnia are also associated with cognitive disturbances and behavioral abnormalities such as hyperphagia, irritability and hypersexuality. Systematic research on the cause of this disease is inexistent, and is urgently needed due to the disabling nature of the disease and the lack of effective treatments. KLS has traditionally been considered an exceptionally rare disease, with fewer than 200 cases reported worldwide over the past 50 years. It now appears to be more common than previously expected. We have identified and characterized over 100 additional cases by active recruitment in the United States, Europe and Israel. The cause of this disease is unknown, but likely involves a major gene. KLS may be disproportionately frequent in the Jewish population, as the largest case series has been reported in this country, accounting for nearly one sixth of all patients reported worldwide. Our recent data from the United States also indicates increased ascertainment of KLS in Ashkenazi Jews, suggesting a genetic founder effect. Results of our recruitment further support the action of genetic factors, as we identified 5 familial cases among our 104 probands (4.8%), extending on case reports of multiplex families published in the literature over the last 40 years. Based on the above and due to the fact that it would be difficult to gather enough multiplex families to conduct traditional linkage studies, we propose to conduct a genome wide association study in 200 trios to identify a major KLS genetic susceptibility locus. A sub-analysis will be performed on 40 Jewish trios to take advantage of the potential founder effect. We will pursue regions of association through fine mapping and in silico analysis of gene content. Finally, we will identify and characterize candidate genes within the critical regions and identify variants in KLS patients. Identification of a Kleine-Levin Syndrome susceptibility locus will help to unravel the pathophysiology of this intriguing disease. This may also lead to novel insights in the control of sleep, appetite and other instinctual behaviors, with potential applications in other periodic neuropsychiatric disorders.

描述(申请人提供)：克莱恩-莱文综合征(KLS)是一种孤儿神经精神障碍，通常始于童年或青春期。它的主要表现是中枢神经系统引起的周期性睡眠亢进(睡眠数量急剧增加)。这些阵发性睡眠过多还与认知障碍和行为异常有关，如吞噬过多、易怒和性欲亢进。目前尚不存在对该病病因的系统研究，而且由于该病的致残性和缺乏有效的治疗方法，迫切需要对其进行系统研究。KLS传统上被认为是一种极其罕见的疾病，在过去的50年里，全世界报告的病例不到200例。现在看来，这种情况比之前预期的更为常见。通过在美国、欧洲和以色列积极招募，我们已经确定了另外100多个病例，并确定了其特征。这种疾病的病因尚不清楚，但可能与一个主基因有关。KLS可能在犹太人群中不成比例地频繁，因为在这个国家已经报告了最大的病例系列，占全世界报告的所有患者的近六分之一。我们最近来自美国的数据还表明，在德系犹太人中，KLS的确认率增加，这表明存在基因创始人效应。我们招募的结果进一步支持了遗传因素的作用，因为我们在104名先证者中发现了5例家族性病例(4.8%)，延续了过去40年来文献中发表的多胎家庭病例报告。在此基础上，考虑到很难收集到足够的多基因家系来进行传统的连锁研究，我们建议在200个三联体中进行全基因组关联研究，以确定一个主要的KLS遗传易感基因座。为了利用潜在的创始人效应，将对40个犹太人三人组进行子分析。我们将通过精细作图和基因含量的电子分析来寻找关联区域。最后，我们将识别和表征关键区域内的候选基因，并识别KLS患者的变异。Kleine-Levin综合征易感基因的确定将有助于揭开这种耐人寻味的疾病的病理生理学。这也可能导致在控制睡眠、食欲和其他本能行为方面的新见解，并有可能应用于其他周期性神经精神障碍。