Achim Kramer, PhD, of the Charité Universitaetsmedizin in 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.
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 pm or 7 pm and rise by 4 am. In 1999, it was discovered that a mutated gene, called PERIOD2 (PER2) is mutated in many cases of FASPS.
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 phosphorylation defects result in the behaviors displayed by well-known circadian mutants in hamsters and fruit flies.