Characterization of Advanced Sleep Phase Syndrome

生物钟无处不在，为我们星球上的生命提供了重要的适应优势。 老年人的睡眠时相提前综合征（ASPS）和青春期的睡眠时相延迟综合征（DSPS）是人类常见的睡眠障碍，具有显著的不良健康后果。 轮班工作、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，对果蝇和啮齿动物昼夜节律起搏器的分子遗传学理解迅速增加，但对人类生物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为我们提供关于人类生物钟如何发生故障的线索。 我们最近报道了第一个孟德尔人类昼夜节律紊乱（家族性ASPS），一个短周期的昼夜节律变异表现为4小时的温度，褪黑激素和睡眠-觉醒节律的相位提前。 我们已经在一个大型ASPS家族中定位并鉴定了致病基因（hPer 2）。 我们还确定了hPER 2区域，其中酪蛋白激酶1 α（CK 1 β）结合，并证明了hPER 2是CK 1 β磷酸化的底物，这是hPER 2磷酸化不足突变的功能结果。 临床和生理表征、遗传学和体外生化分析的结合已经开始阐明人类昼夜节律变化的第一个模型。 我们还确定了20多个额外的ASPS先证者，其中许多人有ASPS家族史，并表明其中几个不映射到第一个ASPS基因座;这些家庭将使我们能够确定其他ASPS基因和突变。 我们正在进行的研究将继续使用临床，遗传和生物化学工具来了解人类生物钟的功能。鉴定引起昼夜节律变化的遗传改变和表征由这些基因编码的变体蛋白将有助于将生物钟的动物模型扩展到人类，并最终可能导致改善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.