Early riser. A newly discovered mutation may cause some people to wake at very early hours.

A Genetic Wake-Up Call

Scientists have identified a second mutation that leads to an inherited form of perpetual jet lag. Sufferers of Familial Advanced Sleep Phase Syndrome (FASPS) get sleepy around 6 p.m. and are wide awake again at 4 a.m. The find gives researchers new insights into the proteins that control sleepiness and provides a promising target for those searching for better and safer sleeping pills or jet-lag treatments.

FASPS was first characterized in 1999, and scientists have been searching since then for the genes that cause it. In 2001, researchers identified a genetic culprit for one family's early-bird tendencies, but because the mutation wasn't found in other families, researchers suspected additional genes might be involved in the condition.

So Ying-Hui Fu of the University of California, San Francisco, and her colleagues kept up the search for changes in genes known to affect the body's 24-hour sleep-wake cycle. In one family with at least five affected members spanning three generations, the team found a mutation in a gene called casein kinase I delta (CKIδ). The pattern wasn't present in family members who had normal sleeping patterns or in 250 control blood samples, report the researchers today in Nature. To get a better idea of how the gene works, the researchers genetically altered fruit flies and mice to carry the human mutation. To their surprise, flies carrying the mutant gene had much longer circadian rhythm periods than normal, while the mice had shorter periods, similar to the human patients. That suggests, says Fu, that although the same genes affect circadian rhythms in flies and humans, they appear to be regulated differently in each organism. The differences are a potentially rich source of information on the intricate workings of the body's internal clock, says Martha Merrow, a chronobiologist at the University of Groningen in the Netherlands.

The discovery may have an impact beyond studies of sleep. The team noticed that carriers of the mutation were also more likely to suffer from depression. That may be because their shifted body clocks leave them socially isolated, but the researchers are working to determine if there may be a biological connection as well, Fu says. The gene also provides a promising target for researchers looking for better ways to help insomniacs and jet-lag sufferers, she says. Because CKIδ belongs to a family of well studied enzymes, it might be fairly easy to find ways to block or enhance its activity.

Related sites
Ying-Hui Fu's & Louis Ptá&#269ek's laboratories of neurogenetics
Information on sleep from NIH