Characterization of Advanced Sleep Phase Syndrome

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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.