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Early to bed, early to rise

In an upcoming G&D paper, a team of German scientists presents a genetic basis for understanding human morning lark behavior. Dr. Achim Kramer (Charit Universitaetsmedizin Berlin) and colleagues have uncovered a genetic cause for the human familial advanced sleep phase syndrome (FASPS), which causes people to both go to sleep and wake up very early.

"Being a morning lark or a night owl is something encoded in people's genes and we here made substantial progress to uncover the molecular basis for that," explains Dr. Kramer.

FASPS is a dominantly inherited circadian rhythm disorder in which patients' inborn biological clock (or circadian clock as it is known by scientists) runs ahead of normal. Circadian clocks are found in organisms ranging from bacteria to humans. They keep our bodies' daily activities, like sleeping and eating, on a roughly 24 hour schedule, or period. FASPS patients' periods are about 4 hours advanced, causing the patients to retire at 6 or 7pm and rise by 4am. In 1999, it was discovered that a mutated gene, called PERIOD2 (PER2) is mutated in many cases of FASPS.

Dr. Kramer and colleagues mapped phosphorylation sites on the PER2 protein. They identified 21 sites, one of which (Serine 659), was implicated in FASPS. By monitoring the bioluminescence cycles of cell lines, the researchers demonstrated that mutation of Serine 659 causes a shortening of the luminescence period and recapitulates the FASPS phenotype. The researchers determined that the mutated form of Serine 659, which does not get phosphorylated, leads to PER2's destabilization and earlier clearance from the cell nucleus.

The research team went on to show that mutations of other PER2 phosphorylation sites have differential effects on PER2 protein stability, circadian period length, and organismal behavior. In fact, using a simple mathematical algorithm modeled after their work, the researchers successfully explained how different PER phosphory
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Contact: Heather Cosel
coselpie@cshl.edu
Cold Spring Harbor Laboratory
19-Sep-2006


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