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| The discovery of a gene
that causes narcolepsy in dogs – making them prone to episodes
of sudden muscle weakness called cataplexy – promises to
aid people who suffer from this same condition. |
AFTER A DECADE-LONG SEARCH, A STANFORD-LED
TEAM HAS IDENTIFIED A GENE THAT CAUSES THE SLEEP DISORDER NARCOLEPSY
– A BREAKTHROUGH PREDICTED TO HELP THOSE WHO SUFFER FROM THE
DISEASE AND TO SHED LIGHT ON TWO OF THE BIGGEST MYSTERIES IN SLEEP
RESEARCH: HOW AND WHY WE SLEEP.
"Narcolepsy is the only known neurological disorder
that affects the brain and sleep in such a dramatic way," says associate
professor of psychiatry Emmanuel Mignot, MD, PhD, director of Stanford's
Center for Narcolepsy. Usually beginning in adolescence, narcolepsy's
symptoms include extreme daytime sleepiness, sleep paralysis and
vivid auditory or visual hallucinations while asleep or while falling
asleep.
The most dramatic symptom, however, is sudden episodes
of muscle weakness known as cataplexy. The knees may buckle and
in extreme cases the person may collapse to the floor completely
paralyzed. Loss of muscle tone can last from a few seconds to several
minutes. These abrupt attacks can occur at any time but are often
triggered by strong emotions such as anger, joy or surprise. It's
common for narcoleptics to have such an attack while laughing.
Narcolepsy ruins lives, Mignot says, especially since
an average of 14 years pass before the disorder is diagnosed. Because
their sleep at night is disrupted, narcoleptics are usually drowsy
during the day. Constant sleepiness often impairs performance in
school and makes it hard to hold down a job. Not surprisingly, narcoleptics
are also accident prone, with about 10 times the rate of auto accidents
as the general population. The exact prevalence of narcolepsy is
unknown, but surveys in Europe, Japan and the United States suggest
about 1 person in 2,000 is affected to some degree.
The researchers, led by Mignot, used a technique
called positional cloning to pinpoint the gene in dogs, one of the
few species besides humans known to develop narcolepsy. In the August
6, 1999, issue of Cell, Mignot and his colleagues report
locating two defective versions of the gene, known as hypocretin
receptor 2, one in Doberman pinschers, the other in Labrador retrievers.
This gene codes for a protein that juts out from the surface of
brain cells and that functions as an antenna, allowing the cell
to receive messages -- transmitted via small molecules called hypocretins
-- from other cells. The defective versions of the gene encode proteins
that cannot recognize these messages, in effect cutting the cell
off from essential directives, including perhaps messages that promote
wakefulness.
The researchers know that the same gene exists in
humans, and they plan to search for defective versions in narcoleptic
patients, Mignot says. He hopes the discovery will lead to improved
therapies for narcoleptics, he says.
Mignot notes that current treatments for narcolepsy
-- doses of stimulants to maintain alertness during the day -- alleviate
some symptoms but do not influence the underlying brain defect.
With the gene in hand, however, it should be possible to design
a drug that can compensate for the failure of the hypocretin system,
Mignot says.
Mignot chose to study dogs in part because the animals
get narcolepsy, but also because the genetics of the canine disorder
are simple in some breeds. In Dobermans and Labradors, narcolepsy
is caused by a single gene, and the trait is recessive, meaning
that an animal must inherit a defective copy of the gene from both
parents to be affected.
In people, the situation is much more complicated
because narcoleptics only rarely have affected relatives. Mignot
says the inheritance of human narcolepsy resembles diseases like
heart disease and diabetes, in which several genes contribute to
susceptibility but the disorder usually will not develop without
a specific environmental trigger.
Finding the gene was particularly challenging, Mignot
says, because little was known about the organization of the dog's
genes. The team gradually narrowed their search, refining their
map of the dog's genes along the way, until they fingered a single
gene on the dog's 12th chromosome.
By implicating hypocretins in sleep regulation, the
work also opens up new areas of research for sleep scientists, Mignot
says. These molecules were known to control eating, but their role
in sleep is unexpected, he says. "Hypocretins are going to be a
major player in the understanding of sleep," he says. -- MITCH LESLIE
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