Issue of
August 11, 1999

Stanford researchers pinpoint gene that causes the sleep disorder narcolepsy

BY MITCH LESLIE

After a decade-long search, a Stanford-led team has identified a gene that causes the sleep disorder narcolepsy -- a breakthrough that brings a cure for this disabling condition within reach, the scientists say.

The researchers, led by Emmanuel Mignot, MD, PhD, associate professor of psychiatry, used a technique called positional cloning to pinpoint the gene in dogs, one of the few species besides humans known to develop narcolepsy. Mignot predicts the finding will not only help the roughly 135,000 Americans who suffer from narcolepsy, but in time it will shed light on two of the biggest mysteries in sleep research: how and why we sleep.

"This discovery is the exciting culmination of 36 years of research on narcolepsy at Stanford," said William Dement, MD, PhD, director of the Sleep Disorders Research Center at Stanford.

"Narcolepsy is the only known neurological disorder that affects the brain and sleep in such a dramatic way," said Mignot, who is director of Stanford's Center for Narcolepsy. It affects both humans and animals and has both genetic and sporadic forms. Usually beginning in adolescence, narcolepsy's symptoms include extreme daytime sleepiness, sleep paralysis -- a frightening inability to move shortly after awakening or shortly after dozing off -- as well as 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, the neck muscles may go slack, 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 said, 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 uncertain, but surveys in Europe, Japan and the United States suggest about 1 person in 2,000 is affected to some degree.

In the August 6 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 said.

"You are happy when you make a discovery, but you are really, really happy when you make a discovery with therapeutic possibilities," Mignot said. He noted 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 said.

Mignot and his colleagues began hunting for the narcolepsy gene in dogs more than a decade ago. They 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. While the disorder occasionally runs in families, most narcoleptics have no affected relatives. Mignot said 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 said, because, unlike the situation with well-studied animals like mice and humans, 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 said. These molecules were known to control eating, but their role in sleep is unexpected, he said. "Hypocretins are going to be a major player in the understanding of sleep," he said.

Mignot's Stanford co-authors are senior research scientist Seiji Nishino, MD, PhD; research coordinator Xiaoyan Lin; research associate Ling Lin, PhD; research assistants Robin Li and Xiaohong Qiu; postdoctoral fellows Juliette Faraco, PhD, and Hiroshi Kadotani, MD, PhD; and undergraduate William Rogers. The final member of the team is Pieter de Jong, PhD, professor of genetics at the Roswell Park Cancer Institute in Buffalo, N.Y. SR