Investigators have found that a relatively common genetic mutation throws off the timing of the biological clock, resulting in a common sleep syndrome called delayed sleep phase disorder.

Patients with delayed sleep phase disorder are unable to fall asleep until very late at night, often after 2 am, and have difficulty getting up in the morning. Research in 2017 discovered a surprisingly common mutation that causes this disorder by altering a key component of the biological clock. These new findings delved deeper, examining the molecular mechanisms involved and pointing toward potential treatments.

Daily cycles in virtually every aspect of our physiology are driven by cyclical interactions of clock proteins in cells, although genetic variations that change the clock proteins can alter the timing of the clock and cause sleep phase disorders. A shortened clock cycle causes people to go to sleep and wake up earlier than normal, whereas a longer cycle results in staying up late and sleeping in later in the morning.

“This mutation has dramatic effects on people’s sleep patterns, so it’s exciting to identify a concrete mechanism in the biological clock that links the biochemistry of this protein to the control of human sleep behavior,” said corresponding author Carrie Partch, PhD, in a press release.

Most clock-altering mutations are rare, according to Partch. Although they are important to understanding the mechanisms of the clock, these mutations may only affect 1 in 1 million people. Despite this rarity, the genetic variant identified in 2017 was found in approximately 1 in 75 people of European descent. Partch added, however, that it remains unclear how often this particular mutation is involved in delayed sleep phase disorder. Because of the complexity of individual sleep habits, diagnosis can be challenging.

The mutation affects the cryptochrome proteins, which are 1 of 4 main clock proteins. According to the investigators, 2 of the proteins form a complex that turns on the genes for the other 2 proteins, which then combine to repress the activity of the first pair, turning them off and starting the cycle again. This feedback loop is the central mechanism of the body’s biological clock.

The cryptochrome mutation causes a small segment of the protein to get left out, and Partch’s lab found that this changes how tightly cryptochrome binds to the first complex. The binding of these protein complexes involves a pocket in which the missing segment normally competes and interferes with the binding of the rest of the complex, according to a press release.

“This genetic marker is really widespread,” Partch said. “We still have a lot to understand about the role of lengthened clock timing in delayed sleep onset, but this one mutation is clearly an important cause of late-night behavior in humans.

Partch added that ongoing research on treatments should target that pocket in order to shorten the clock for people with delayed sleep phase disorder.

REFERENCE
Scientists discover how a common mutation leads to ‘night owl’ sleep disorder [news release]. EurekAlert; October 27, 2020. https://www.eurekalert.org/pub_releases/2020-10/uoc--sdh102620.php. Accessed November 6, 2020.