Flawed Gene Blamed For Sleeping Disorder

Letting sleeping dogs lie may be good advice, but in tomorrow's Cell, researchers describe a payoff for studying narcoleptic dogs: They've found the genetic mutation responsible for the chronic sleeping condition. The researchers say a similar gene may cause the disorder in people, and if so, it could lead to new treatments--or to new sleeping pills.

Narcoleptics spontaneously fall asleep, often at inopportune moments--even while laughing at a joke, or in the middle of an angry outburst. Other symptoms include general drowsiness and sleep paralysis, a fleeting inability to move after waking up. The cause of the disorder remains a mystery, but evidence suggests that at least some people inherit it: Sufferers often have a specific DNA sequence in a gene that codes for an immune system protein. Because dogs appeared to inherit the disorder through a single mutation, Emmanuel Mignot and his colleagues at Stanford University Medical Center decided to sniff around in canine DNA for the flawed gene.

Using gene mapping techniques, the researchers zeroed in on a mutation in the gene for hypocretin receptor 2. Similar mutations, it turned out, appear in both Doberman pinschers and Labrador retrievers bred for narcolepsy. First identified in humans early last year, hypocretin receptor 2 was tentatively linked by other researchers to metabolism. A possible connection to narcolepsy isn't as strange as it might seem. Rats deprived of sleep lose the ability to regulate metabolism--they eat twice the normal amount of food, but still lose weight. Given the receptor's clear link to narcolepsy, Mignot says sleep regulation is probably it's most important function.

Experts hail the finding. The hypocretin receptor 2 gene could be the single most important gene in human narcolepsy, says Michael Aldrich, a neurologist and director of the University of Michigan's Sleep Disorders Center. Hypocretin--which binds to hypocretin receptor 2--is manufactured in large quantities in some parts of the hypothalamus, an area known to be important in regulating sleep. Thus hypocretin, Mignot says, may tell the brain to stay awake and alert.

Mignot and his colleagues have begun population studies to see whether hypocretin receptor 2 mutations appear in narcoleptic people. If so, he says, researchers might be able to design a drug that could compensate for the faulty receptor. Conversely, a drug that blocks the receptor could make a very popular sleeping pill. "Many people would love to fall asleep the way narcoleptics do, at least temporarily," Mignot says.

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