Characterization of Advanced Sleep Phase Syndrome

生物生物钟无处不在，为地球上的生命提供了重要的适应优势。老年晚期睡眠阶段综合征（ASPS）和青春期睡眠阶段延迟综合征（DSPS）是人类常见的睡眠障碍，具有严重的不良健康后果。倒班工作、时差和盲人的自由奔跑节奏也是重要的昼夜节律紊乱。尽管在过去的十年中，对果蝇和啮齿类动物的昼夜节律起搏器的分子遗传学理解迅速增加，但对人类时钟的工作原理知之甚少，主要是因为没有自然发生的突变可以给我们提供关于人类时钟如何故障的线索。我们最近报道了首例孟德尔人类昼夜节律紊乱（家族性ASPS），这是一种短周期的昼夜节律变异，表现为温度、褪黑激素和睡眠-觉醒节律提前4小时。我们已经在一个大的ASPS家族中定位并鉴定了致病基因（hPer2）。我们还确定了酪蛋白激酶1epsilon （CK1epsilon）结合的hPER2区域，并证明hPER2是CK1epsilon磷酸化的底物；hPER2低磷酸化突变的功能后果。结合临床和生理特征，遗传学和体外生化分析已经开始阐明人类昼夜节律变化的第一个模型。我们还发现了20多个额外的ASPS先证者，其中许多人有ASPS家族史，并表明其中一些不映射到第一个ASPS位点；这些家族将使我们能够识别额外的ASPS基因和突变。我们正在进行的研究将继续使用临床、遗传和生化工具，努力了解人体时钟的功能。鉴定导致昼夜节律变化的遗传改变和鉴定由这些基因编码的变异蛋白将有助于将昼夜节律钟的动物模型扩展到人类，并最终可能导致改进人类昼夜节律紊乱的诊断和治疗。

Biological circadian clocks are ubiquitous and provide important adaptational advantages to life on our planet. The advanced sleep-phase syndrome (ASPS) of aging and the delayed sleep-phase syndrome )DSPS) of adolescence are common human sleep disorders that have significant adverse health consequences. Shift work, jet lag, and free-running rhythms of the blind are also important circadian dysrhythmias. Despite a rapid increase in molecular-genetic understanding of circadian pacemakers in Drosophila and rodents over the past decade, very little is known about the workings of the human clock, largely because no naturally occurring mutations are available to give us clues about how the human clock can malfunction. We recently reported the first Mendelian human circadian rhythm disorder (familial ASPS) a short period circadian rhythm variant manifest by a 4 hour phase advance of the temperature, melatonin and sleep-wake rhythms. We have mapped and identified the causative gene (hPer2) in one large ASPS family. We have also identified the hPER2 region where casein kinase 1epsilon (CK1epsilon) binds and demonstrated that hPER2 is a substrate for phosphorylation by CK1epsilon; the functional consequence of the mutation of hypophosphorylation of hPER2. The combination of clinical and physiological characterization, genetics, and in vitro biochemical analysis has begun to shed light on first model of circadian rhythm variation in humans. We have also identified over 20 additional ASPS probands, many of whom have family histories of ASPS, and shown that several of these do not map to the first ASPS locus; these families will allow us to identify additional ASPS genes and mutations. Our ongoing studies will continue to use clinical, genetic, and biochemical tools to work toward an understanding of how the human clock functions. Identification of genetic alterations causing circadian rhythm variation and characterization of variant proteins encoded by such genes will help extend animal models of circadian clocks to human and eventually may lead to improved diagnosis and treatment of human circadian disorders.