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UCSF study offers insight into human circadian rhythms

31.03.2005


Scientists have identified a gene and mutation within it that causes a rare sleep behavior, in which individuals have a "fast" biological clock. The gene’s enzyme could lead to a therapeutic target for the disrupted sleep patterns seen in such groups as those facing jet lag or nighttime work shifts.



More broadly, the gene provides a probe for exploring the regulatory mechanisms of the body’s internal biological clock, or circadian rhythms -- a waxing and waning of genetic, biochemical and physiological processes that occurs in a 24 hour period -- about which little is known in humans at the molecular level.

As the findings hint that the genetic mutation might play a role in depression, the scientists are now exploring this possibility, as well.


"Evidence suggests that circadian rhythms may have a fundamental role in numerous behaviors," says Ying-hui Fu, PhD, associate professor of neurology at University of California, San Francisco and the senior author of the paper. "As the enzyme produced by the gene modulates many proteins, we may test for its impact on novelty seeking and learning and memory, too."

"The discovery of the gene opens the window just a crack, but it could let in a lot of light for probing the neurobiology of the brain," says co-senior author Louis Ptacek, MD, a Howard Hughes Medical Institute investigator and UCSF professor of neurology.

The finding, published in the March 31 issue of Nature, builds on previous research led by Ptacek and co-author Christopher Jones, PhD, associate professor of neurology at University of Utah. In 1999, in a study of three families with the unusual sleep pattern, known as familial advanced sleep phase syndrome (FASPS), the scientists created a family tree to map the incidence of inheritance, and made the seminal finding that the behavior was a single-gene trait. (Nature Medicine, Sept. 1999). In 2000, the team discovered the gene (hPer2) responsible for the condition in one particular family, the first report of a human circadian rhythm gene. (Science, Jan. 12, 2001).

The breadth of the knowledge coming out of the current study is somewhat unique, says Ptaceck. "I’m not aware of another study that has gone from the human to the fly to the mouse in a single study. It demonstrates of the combined power of human molecular genetics research and studies in animals."

The study began with the scientists isolating, or cloning, the mutant gene responsible for causing FASPS in five members of an extended family. The gene is known as casein kinase1 delta (ck1 delta); the mutated form is designated CK1 delta-T44A. They made the discovery by taking blood samples of the individuals and then using linkage analysis to hone in on the region of DNA within the chromosomes most likely to reveal the relevant gene, based on what was known about other genetic markers related to circadian rhythms. The gene was found on chromosome 17. (The mutated form was compared to the gene in family members who did not have FASPS.)

Next, they determined that, in a test tube, the activity of the enzyme (CK1 delta) encoded by the mutated gene was decreased.

Finally, to explore the effect of the genetic mutation on circadian activity, the scientists inserted the mutated human gene into the nerve cells of the circadian clock in the fruit fly Drosophila melanogaster and the mouse. Scientists have learned much about human gene function by studying animals, given the many genes that have been conserved through evolution, and both animals have been a key source of information regarding the genetic and molecular biology of circadian rhythms.

As expected, the transgenic mice displayed the same abnormal sleeping pattern seen in the human cases of FASPS, as measured in the decrease in their wheel-running activity.

Unexpectedly, however, the result was the opposite in the transgenic flies, as displayed by its extended locomotor activity. The scientists do not know what accounts for the difference.

"The findings suggest that, although many individual parts of the circadian rhythm clock are conserved across species, fundamental differences exist," says the first author of the study, Ying Xu, PhD, a visiting postdoctoral fellow in the Fu lab. "These models provide the opportunity to begin study of the similarities and differences between circadian clocks in model organisms and humans."

While the internal clock of most people operates in just over a 24-hour time period, the clock of those with FASPS advances an average of 45 minutes a day. If left unchecked, it would continue to speed up. Due to the social demands and needs of those with the disorder, it is kept in check to a relative degree.

The creation of the transgenic mouse model provides a tool for exploring how the CK1 delta-T44A enzyme causes FASPS. It also offers a model for testing promising compounds directed at the enzyme to treat a variety of sleep disorders, whether resulting from biological or environmental factors.

While FASPS is caused by an individual gene, other forms of sleep-pattern disturbances, such as the tendency for some elderly to wake up earlier than normal ("advanced sleep phase syndrome"), could be caused by "epigenetic" factors, which involve changes in gene expression rather than a mutation in a gene.

Finally, the potential insights extend beyond those involving sleep. Four of the five individuals in the study have clinical features or a history of depression. While the scientists say that this could be a coincidence, or that the depression is situational, i.e., due to being "out of phase with the rest of the world," the more provocative possibility, they say, is that circadian rhythm variants contribute to psychiatric disorders.

Now, in collaboration with UCSF’s Larry Tecott, MD, PhD, UCSF associate professor of psychiatry and a member of the UCSF Center for Neurobiology and Psychiatry, the team is planning to use a mouse model of depression to study the gene.

"Whether or not it is in fact caused by this particular mutation remains to be tested, but the creation of animal models of the human circadian gene variant will allow direct testing of this fascinating and important hypothesis," says Fu.

Other hypotheses are also on the horizon: The team noted that five of the family members who have FASPS, as well as a sixth relative with possible FASPS, have asthma and migraine with aura (a neurological sensation that foretells the onset of a migraine). While they have not investigated a possible link, the scientists have taken note.

"We’re going to follow the same approach we always have," says Ptacek. "If we find something interesting in any of these domains, we’ll pursue."

Other co-authors of the study were Quasar S. Padiath, Susan C. Wu , Noriko Saigoh, of the UCSF Department of Neurology; Kazumasa Saigoh, formerly of the UCSF Department of Neurology; and Robert E. Shapiro of the Department of Neurology, University of Vermont College of Medicine.

Jennifer O’Brien | EurekAlert!
Further information:
http://www.ucsf.edu

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