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Some of us may decide to live by an "early to bed and early to rise" routine, but certain people—those with a particular genetic mutation—have no choice. Individuals with familial advanced sleep-phase syndrome (FASPS) are the ultimate early birds, awakening in the wee hours of the morning (by 4 a.m. or so), then turning desperately tired just as prime-time TV is about to begin.
FASPS occurs in people with a rare variant in a gene implicated in regulating the body's internal clock. That gene, called human Period 2 (Per2), is one of a small number of genes that influence the length of the circadian rhythm cycle governing sleep. Ordinarily, the body's clock runs on a timetable that nearly matches the 24-hour day, sounding a biochemical alarm in the morning that calls the slumbering brain to action. But a variant in the Per2 gene can shorten and displace the ordinary circadian cycle, causing those possessing it to wake up extra early, according to HHMI investigator Louis J. Ptáček of the University of California, San Francisco.
Per2's machinations have recently been rendered less mysterious by work in Ptáček's lab, in collaboration with the UCSF lab of Ying-Hui Fu, using mice implanted with human versions of the gene. Their insights are helping to explain the genetics and biochemistry of sleep in normal people as well. Ultimately, the research could lead to new drugs for sleeping disorders or for coping with jet lag and shift work.
In a normal sleep cycle, Per2 codes for a protein that builds up during sleep time until it surpasses a threshold level, thereby triggering biochemical signals to inactivate the gene. The PER2 protein then gradually decomposes until its levels drop so low that the gene is reactivated, restarting the wake-sleep cycle.
A key chemical governing production and destruction of this protein is the enzyme casein kinase I (CKI), which attaches phosphate groups to it. Depending on where the phosphate is attached, the result is either increased production or faster destruction of the protein. "We believe this is a way the clock is really fine-tuning the system," says Ptáček.
CKI cannot enhance PER2 protein production, though, unless a phosphate has already been attached at link 662 in the protein s chain of amino acids. That phosphate is installed with the help of an as-yet-unidentified priming enzyme.
In a normal PER2 protein, position 662 is occupied by the amino acid serine, which is happy to accept the phosphate provided by the mystery enzyme. But in people with FASPS, position 662 is occupied by glycine, an amino acid that refuses to have anything to do with phosphate. Thus, the mystery enzyme is powerless to attach the phosphate, which in turn means that CKI can no longer stimulate PER2-protein production. But CKI continues to facilitate protein destruction, the transgenic mouse studies show. Thus, protein levels fall faster, making the circadian period shorter and causing early awakening, just as in humans with FASPS.
The latest work, published in the January 12, 2007, issue of Cell by Ptáček and Fu with collaborators from China, Singapore, and the University of Utah, has gone a long way toward teasing out the molecular intricacies underlying Per2's function. Now someone needs to identify the mystery priming enzyme. "I think it will be an outstanding candidate for drugs to modulate the circadian period," Ptáček says.
That will be good news to some people with FASPS, at least those bothered by their condition. "I don't call this a disease," he says. "It's a behavioral trait, a behavioral variant. Some people do not like it they think it s a disease and would do anything possible to fix it if we could do that." Yet others, he says, find early rising an advantage that actually does pave the way to health, wealth, and wisdom.
"Whether it's a good or bad thing," says Ptáček, "really depends on the person's perspective."
—T.S.
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