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Advanced sleep phase syndrome (ASPS), also known as the advanced sleep-phase type (ASPT) of circadian rhythm sleep disorder, is a condition in which patients feel very sleepy early in the evening (e.g. 18:00-19:00) and wake up very early in the morning (e.g. 03:00).
ASPS is frequently encountered in the elderly and in post-menopausal women. It can be treated pharmacologically, with evening bright lights, or behaviorally with chronotherapy or free-running sleep.
In 1999, Louis Ptácek’s research group at the University of California, San Francisco reported findings of a human circadian rhythm disorder showing a familial tendency. The disorder was characterized by a life-long pattern of sleep onset around 7:30pm and offset around 4:30am. Among three lineages, 29 people were identified as affected with this familial advanced sleep-phase syndrome (FASPS), and 46 were considered unaffected. The pedigrees demonstrated FASPS to be a highly penetrant, autosomal dominant trait.[1]
Two years after reporting the finding of FASPS, Ptácek’s and Fu’s groups published results of genetic sequencing analysis on a family with FASPS. They genetically mapped the FASPS locus to chromosome 2q where very little human genome sequence was then available. Thus, they identified and sequenced all the genes in the critical interval. One of these was Period2 (Per2). Sequencing of the hPer2 gene revealed a serine-to-glycine point mutation in the CKI binding domain of the hPER2 protein that resulted in hypophosphorylatin of Per2 in vitro.[2]
In 2005, Fu’s and Ptácek’s labs reported discovery of a different mutation causing FASPS. This time, CKId was implicated, demonstrating an A-to-G missense mutation that resulted in a threonine-to-alanine alteration in the protein.[3] The evidence for both of these reported causes of FASPS is strengthened by the absence of said mutations in all tested control subjects and by demonstration of functional consequences of the respective mutations in vitro. Fruit flies and mice engineered to carry the human mutation also demonstrated circadian phenotypes although the mutant flies had a long circadian period while the mutant mice had a shorter period.[2][3] The differences between flies and mammals that account for this difference are not known. Most recently, Ptácek and Fu reported additional studies of the human Per2 S662G mutation and generation of mice carrying the human mutation. These mice had a circadian period almost 2 hours shorter than wild-type animals. Genetic dosage studies of CKId on the Per2 S662G mutation revealed that CKId is having opposite effects on Per2 levels depending on the sites on Per2 that CKId is phosphorylating.[4]
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