Probing genetics and biology of human sleep homeostasis

项目摘要 家族性自然短睡眠(FNSS)是一种罕见的孟德尔睡眠形式，受影响的人会终身睡眠 对睡眠的需求明显低于普通人。这些人通常每晚睡4-6个小时 晚上还没有报告感觉休息得很好。2009年，我们报道了第一个人类FNSS特征，即病因的鉴定 基因/突变。以及在建模的小鼠中类似的短睡眠表型的特征(以及相应的 果蝇的休息-活动表型)。自那以后，我们已经确认了90多名FNSS先驱，并一直在 通过对其他受影响和未受影响的家庭进行表型分析和DNA库来扩大这些家庭 会员。随后的完整外显子组测序(WES)确定了2个候选基因/突变(2个中各有1个 家庭)。在这两种情况下，我们都产生了人类突变的小鼠模型。这两只老鼠也都显示出 在人类受试者中可见的短睡眠表型。另一种基因(GRM1)被发现含有明显的突变 在两个不同的家庭。一个GRM1等位基因的小鼠模型也通过脑电显示睡眠时间短。这4个基因 (DEC2、ADRB1、NPSR1和GRM1)仍然只能解释最初接受WES的约30个家系中的一小部分。 在这项提案中，我们计划继续从现有的“不明原因”家庭中收集FNSS对象，并继续 收集新的先驱和他们的家人。我们不断增长的数据库是一个令人难以置信的资源，用于识别 通过全外显子组测序和全基因组测序获得额外的FNSS基因/突变。对这方面的研究 越来越多的FNSS基因将帮助我们和其他人更好地了解 有助于调节睡眠和提高效率。最终，对这种生物途径的理解可能会导致 开发更好的药物以改善睡眠质量和效率的新目标。

Project Summary Familial Natural Short Sleep (FNSS) is a rare Mendelian form of sleep where affected individuals have a lifelong requirement for sleep that is significantly less than the average person. These people often sleep 4-6 hours per night yet report feeling well-rested. In 2009, we reported the first human FNSS trait, identification of the causative gene/mutation. and characterization of a similarly short sleep phenotype in modeled mice (and a corresponding rest-activity phenotype in Drosophila). We have since identified over 90 FNSS probands and have been expanding these families with phenotyping and DNA banking of additional affected and unaffected family members. Subsequent whole exome sequencing (WES) identified 2 candidate genes/mutations (1 in each of 2 families). In both cases, we've generated mouse models of the human mutations. Both of these mice also show short sleep phenotype as seen in human subjects. Another gene (GRM1) was found to harbor distinct mutations in 2 different families. A mouse model of one GRM1 allele also shows short sleep by EEG. These 4 genes (DEC2, ADRB1, NPSR1, and GRM1) still only explain a minority of the ~30 families that underwent initial WES. In this proposal, we plan to continue collecting FNSS subjects from existing `unexplained' families and to continue collecting new probands and their families. Our growing database is an incredible resource for identifying additional FNSS genes/mutations via whole exome sequencing and whole genome sequencing. Studies of this growing list of FNSS genes will help us and others to better understand pathways and brain circuits that contribute to sleep regulation and efficiency. Ultimately, understanding of such biological pathways may lead to novel targets for developing better drugs to improve sleep quality and efficiency.