Researchers discover how a typical mutation contributes to ‘evening owl’ sleeping disorder

A new study by researchers at UC Santa Cruz shows what sort of genetic mutation throws off the timing of the biological clock, causing a typical sleep syndrome called delayed sleep phase disorder.

People with this specific condition can’t get to sleep until late through the night (often after 2 a.m.each morning ) and also have difficulty getting up. In 2017, scientists discovered a surprisingly common mutation that creates this sleep disorder by altering an extremely important component of the biological clock that maintains your body’s daily rhythms. The newest findings, published October 26 in Proceedings of the National Academy of Sciences, reveal the molecular mechanisms involved and point the true way toward potential treatments.

“This mutation has dramatic effects on people’s sleep patterns, therefore it is exciting to recognize a concrete mechanism in the biological clock that links the biochemistry with this protein to the control of human sleep behavior,” said corresponding author Carrie Partch, professor of biochemistry and chemistry at UC Santa Cruz.

Daily cycles in just about any part of our physiology are driven by cyclical interactions of clock proteins within our cells. Genetic variations that change the clock proteins can modify the timing of the reason and clock sleep phase disorders. A shortened clock cycle causes individuals to get to sleep and wake up prior to when normal (the “morning lark” effect), while an extended clock cycle makes people stay up late and sleep in (the “night owl” effect).

Most of the mutations proven to alter the clock have become rare, Partch said. They’re crucial that you scientists as clues to understanding the mechanisms of the clock, but certain mutation might only affect one in a million people. The genetic variant identified in the 2017 study, however, was present in around one in 75 individuals of European descent.

How often this kind of mutation is associated with delayed sleep phase disorder remains unclear, Partch said. Sleep behavior is complex — people stay up late for a lot of different reasons — and disorders may be hard to diagnose. And so the discovery of a somewhat common genetic variation of a sleep phase disorder was a striking development.

“This genetic marker is truly widespread,” Partch said. “We still have too much to understand in regards to the role of lengthened clock timing in delayed sleep onset, night behavior in humans but that one mutation is clearly a significant cause of late.”

The mutation called cryptochrome, certainly one of four main clock proteins. Two of the clock proteins (CLOCK and BMAL1) form a complex that turns on the genes for one other two (period and cryptochrome), which combine to repress the experience of the very first pair then, thus turning themselves off and again starting the cycle. This feedback loop could be the central mechanism of the biological clock, driving daily fluctuations in gene activity and protein levels through the physical body.

The cryptochrome mutation causes a tiny segment on the “tail” of the protein to have omitted, and Partch’s lab unearthed that this changes how tightly cryptochrome binds to the CLOCK:BMAL1 complex.

“The location that gets snipped out actually controls the game of cryptochrome in a fashion that contributes to a 24-hour clock,” Partch explained. “Without it, daily cryptochrome binds more tightly and stretches out along the clock.”

The binding of those protein complexes involves a pocket where in actuality the missing tail segment normally competes and disrupts the binding of other complex.

“How tightly the complex partners bind for this pocket determines how quickly the clock runs,” Partch explained. “This tells us we have to be trying to find drugs that bind compared to that pocket and will serve exactly the same purpose since the cryptochrome tail.”

Partch’s lab happens to be doing exactly that, conducting screening assays to spot molecules that bind to the pocket in the clock’s molecular complex. “We all know now that we must target that pocket to produce therapeutics which could shorten the clock if you have delayed sleep phase disorder,” she said.

Partch has been studying the molecular structures and interactions of the clock proteins for decades. This season in research published earlier, her lab showed how certain mutations can shorten clock timing by affecting a molecular switch mechanism, morning larks making many people extreme.

She said the newest study was inspired by the 2017 paper on the cryptochrome mutation from the lab of Nobel Laureate Michael Young at Rockefeller University. The paper had just emerge when first author Gian Carlo Parico joined Partch’s lab as a graduate student, and he was determined to find out the molecular mechanisms accountable for the mutation’s effects.