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Mutation Found in Those Who Sleep Fewer Hours


doi: 10.1097/01.NT.0000361415.04185.24
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In genotype assays, investigators identified a mutation in two members of the same family who sleep fewer hours than normal.

Investigators exploring the mysteries of sleep have identified a mutation — DEC2—in two members of the same family who have shorter daily sleep times than normal.

“Our studies suggest that this mutation results in twenty to 25 percent less sleep,” said the lead study author Ying-Hui Fu, PhD, a professor of neurology at the University of California-San Francisco.

Dr. Fu started her work on circadian rhythms at the University of Utah, and this most recent finding, published in the Aug. 14 Science, reflects collaborative work with investigators at both universities.



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Dr. Fu and her colleagues began to study circadian sleep rhythms more than a decade ago when a woman complained to neurologists at the sleep center that she and other family members would fall asleep at 7 PM and awaken at 3 or 4 AM. Her daughter and granddaughter had a similar sleep schedule.

Dr. Fu's collaborator, Louis Ptáek, MD, collected blood from the family and used whole genome linkage analysis to look for a genetic mutation that could explain this shift in the normal circadian cycle. In a 2001 paper in Science, they described a mutation in the PER2 gene. In the middle of the protein a single amino acid changed from serine to glycine. When they knocked out the gene in mice, they lost natural sleep rhythms, and when they engineered the mice to carry the human mutation, the mice showed the same abnormal sleep pattern as humans carrying the mutation.



After publication of the PER2 findings, the Utah scientists were inundated with calls from people with unusual sleep problems; they either had changes in their sleep schedule or did not need as much sleep. For the last eight years they have been working to identify genes that may play a role in aspects of the sleep cycle.



In genotype assays, they identified the mutation in two members of the same family; but the mutation did not show up in more than 250 control DNA samples. The mutation is a single amino acid change; proline has been replaced with arginine. DEC2 is a transcriptional repressor known to regulate length of sleep in mammals.

Because the mutation appeared in only two people, they wanted to determine whether the natural short sleep trait was caused by the DEC2 mutation. They engineered the gene in mice and monitored them with EEG and EMG to determine whether they were indeed sleeping less. They were. In fact, the animals had slept less in both REM and non-REM sleep modes compared to animals with a normal DEC2 gene.

The new gene mutation, DEC2, does not cause a phase change. It leads to shortened sleep. But it is not clear whether carriers need less sleep or something is just waking them up earlier than normal.

“The field has learned during the last two decades a lot about circadian rhythms, but we still know very little about the sleep homeostasis mechanism,” said Dr. Fu. “As we understand more about how sleep quality and quantity are regulated, we can come up with better treatments for sleep problems.”

These scientists hope that by understanding these genes and the pathways involved in homeostasis they can begin to ask questions about the impact fewer hours has on health, cognition, and behavior. “If we don't get enough sleep, can we compromise our health?” asked Dr. Fu. She said that there is evidence that people who do not sleep enough are prone to mental and physical problems. Dr. Fu said that she and her colleagues also want to figure out if there is a way to modulate sleep homeostasis in a safe way.

That DEC2 is a transcription factor suggests that it has effects on many genes. The scientists are now looking for other genes related to shortened sleep.

“It is an exciting and interesting advance,” said Clifford B. Saper, MD, PhD, the James Jackson Putnam Professor of Neurology and Neuroscience at Harvard Medical School and chairman of neurology at Beth Israel Deaconess Medical Center. “It is particularly interesting that the DEC2 gene, which was thought to have circadian effects, also appears to have effects on sleep homeostasis. The mechanism for this latter effect has to be worked through.”

Years ago, Dr. Saper knocked out a small group of brain cells in laboratory rats, creating a generation of insomniacs. When a knot of cells in the ventrolateral preoptic nucleus in the hypothalamus region were destroyed, the animals' sleep time was cut by 60- to 70-percent. Without that small population of neurons, the rats slept about four hours a day, from a norm of 12 hours. The alert animals did not seem adversely affected by the lack of sleep.

“We don't know how they felt, but there were no changes in eating or in body temperature. They looked normal,” Dr. Saper said.

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• He Y, Jones CR, Fu YH, et al. The transcriptional repressor DEC2 regulates sleep length in mammals. Science 2009;4;325(5942):866–870.
    • Toh KL, Jones CR, Fu YH, et al. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 2001;9;291(5506):1040–1043.
      ©2009 American Academy of Neurology