University of Vermont

University Communications

Gene Mutation Linked to Extra-Early Body Clock, Health Conditions

Release Date: 03-31-2005

Author: Jennifer Nachbur
Phone: 802/656-7875 Fax: 802-656-3961

Geneticists from the University of California, San Francisco, University of Vermont and University of Utah have uncovered a new gene mutation that causes familial advanced sleep phase syndrome (FASPS) – an inherited condition in which sufferers are such ‘early birds’ that they struggle to function in society. Their research findings are reported in the March 31 issue of the journal Nature.

The team of scientists, including Robert Shapiro, M.D., Ph.D., associate professor of neurology at the University of Vermont, studied three generations of a Vermont family in which five members are affected by FASPS. The body clock of each of the five is tuned to a day-length shorter than normal; on average, they wake at around 4 a.m. and go to sleep at about 6 p.m. The family members carry a mutation in the casein kinase I delta (CKId) gene, which interferes with the protein believed to have a key role in regulating the body clock.

Every animal cell has a molecular machinery to tell the time of day. Many of the details of these mechanisms have been identified in fruit flies. Particular nerve cells in the brain act as master time-keepers to ensure that the whole organism is appropriately coordinated with the actual time of day.

In the study, researchers tested the DNA of the affected individuals in the Vermont family and found that the same gene that is important to fruit fly clocks possessed a mutation that is not present in unaffected family members or others. The CKId gene usually codes for a protein enzyme that is able to regulate the functions of other cellular molecules by attaching a phosphorus molecule to them, which is called phosphorylation. The mutated CKId in the FASPS family is not able to phosphorylate other molecules as effectively or efficiently as normal CKId. The consequence is that the molecular clocks run more quickly than normal in people with this mutation.

Mice given a copy of the faulty gene also became ‘morning mice’, the researchers add. But fruit flies subjected to a similar treatment actually showed a lengthened body clock cycle, making them more ‘night owl’ than ‘morning lark’. This shows that although mammal and insect body clocks feature many of the same proteins, their mechanisms may be quite different.

The research team is further studying the Vermont family members with the CKId mutation, because they typically also have other medical conditions including migraine and asthma. They hope to find out whether a reduction in the function of CKId resulting from this mutation will also predispose people to these other conditions since CKId is known to have other functions in cells apart from its role in the molecular clock.

In addition to Shapiro, co-authors on the study include Ying-Hui Fu, Ying Xu, Quasar Padiath, Susan Wu, Noriko Salgoh, Kazumasa Saigoh and Louis Ptacek of University of California, San Francisco; and Christopher Jones of the University of Utah.