Early to bed and early to rise may be a prescription for prosperity, but for some morning larks, it's an unfortunate condition written in their genes. These people suffer from familial advanced sleep phase syndrome (FASPS), a rare condition in which people hit the hay and wake up about four hours before everyone else. A simple expulsion of protein from the cell nucleus seems to be at the root of the syndrome, report researchers who studied the way that a previously identified mutant protein behaved in cultured human skin cells.
The circadian clock is our body's inborn tool for keeping us on a roughly 24-hour schedule, sleeping and eating at regular intervals, but it can go awry. In many of those with FASPS, researchers had identified a mutation in a protein called PERIOD2. Some hypothesized that the mutant protein's effects arise from the lack of a key phosphate group, but nobody had identified a mechanism, says circadian researcher Achim Kramer of Charit¿ Universitätsmedizin Berlin.
Proteins of PERIOD2's family are thought to be more stable when studded with fewer phosphates, but Kramer and co-workers discovered that in this case the opposite is true. The team's research, published online September 18 in Genes and Development, found that the mutant protein degrades more than twice as fast, apparently because it is quickly transported from the nucleus to the cytoplasm, which is rife with protein-digesting enzymes. "Usually the protein is made in the cytosol, and then it goes into the nucleus and inhibits its own synthesis," Kramer explains. The inhibition erodes as the protein is pumped back outside the nucleus. Because the mutant protein exits the nucleus faster, the inhibition is neutralized earlier, resulting in a sped-up cycle. "This is the first example where you can really explain on a molecular level a human behavior," Kramer says.
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Others see the result as a useful step forward. It helps researchers understand "how this exquisite regulation of the clock is being modified," says sleep geneticist Louis Ptacek of the University of California, San Francisco. Animal studies should better determine how different phosphate groups contribute to the protein's effects in live organisms, he adds.
