Gene CRY1 variant alters circadian clock contributing to delayed sleep phase disorder, study finds

If all your life, you have been functioning best in the evening and night, compared to the mornings, a gene mutation may be the cause.

In an article published in the journal Cell on April 6th, researchers from The Rockefeller University reported that a variant of the gene CRY1 slows down the function of the body clock—called the circadian clock—that regulates the sleep-wake cycle. The report says that people with Delayed Sleep Phase Disorder (DSPD) have a longer circadian cycle than most others, making them stay awake during the night.

“Compared to other mutations that have been linked to sleep disorders in just single families worldwide, this is a fairly impactful genetic change,” said senior author Michael W. Young, the Richard and Jeanne Fisher Professor, and head of Rockefeller’s Laboratory of Genetics. The new study reveals that the mutation may be present in up to 1 in 75 people of certain populations.

The Centers for Disease Control and Prevention has reckoned that between 50 and 70 million adults in the US have DSPD—ranging from insomnia to narcolepsy—making them vulnerable to chronic conditions such as diabetes, obesity, and depression.

DSPD disrupts the sleep-wake cycle and make sufferers energetic for a longer time than other people. People who are often diagnosed with DSPD classify themselves as night owls.

Going late to sleep has its own drawbacks. Most people with DSPD find it difficult to wake up early to attend school or work in time. Their bodies do not cooperate and they are forced to wake up, which makes them feel tired and weak during the day and leads to sleeplessness during night.

Young’s lab has researched the internal body clock for more than 30 years, categorizing the number of genes involved in keeping flies, human beings, and other animals on a time schedule when it comes to eating and sleeping.

Young, along with research associate Alina Patke (the first and co-corresponding author of the new paper), worked in partnership with sleep researchers at Weill Cornell Medical College to discover whether mutation in any known circadian genes were associated with DSPD. The subjects completed a 14-day period of isolation during which eating and sleeping was permitted whenever they were inclined. Researchers also obtained skin biopsies from each subject.

Most individuals will follow, roughly, a 24-hour circadian rhythm when exposed to such a free-run setting.  One DSPD subject that stayed up late and had a cycle that was approximately half an hour longer caught the attention of the researchers. Several circadian abnormalities such as changes in body temperature and hormones, evening increase in serum melatonin (a sleep regulator) were also posponed.

Young said Melatonin levels started increasing around 9 or 10 pm in most people, whereas in the DSPD patient it did not happen until 2 or 3 am the next morning.

While examining the DNA of the DSPD patient, researchers noticed a variant in the CRY1 allele, a gene that had already been associated with the 24-hour rhythm.

A handful of genes turn on and off over a 24-hour cycle in a healthy body clock. The protein made by CRY1 is in charge of repressing some of these genes during certain components of the cycle. But Young and Patke revealed that the mutation recognized in the patient made the CRY1 protein more active than usual, keeping other clock genes switched off for a longer duration.

The researchers extended the study to other members of the patient’s family. It was discovered that five relatives shared the mutation in CRY1, and all of them had indications of DSPD or a track record of continual sleep problems.

Young’s team extended the study to large genetic databases across the world to decide the occurrence of CRY1 mutations. With a partner in Turkey, they first recognized CRY1 mutation in many families that are not related and in dozens of the Turkish population. After making contact with them and administering interviews and questionnaires, the researchers confirmed that 38 people reported aberrant sleep behavior, while unusual sleeping behaviors were not noticed in their relatives who did not have CRY1 mutation.

Lastly, after searching larger genetic databases for CRY1 mutations, Young’s group considered that as many as 1 in 75 people of non-Finnish European descent have at least one copy of the DSPD mutation. The mutation is dominant, which means that having just one copy of it can cause a sleep disorder.

The research group said that at present there is no proven benefit for those diagnosed with DSPD in being tested for CRY1 mutation. Patke mentioned that just finding the cause does not straight away fix the problem, however, based on this mechanism the development of drugs in the future is not inconceivable.

At the moment, many DSPD patients are managing their sleep-wake cycles by going to bed sooner than their body wants—adopting strict schedules.

“It’s a bit like cigarette smoking in that there are things we can do to help the problem before turning to drugs,” said Young. He also added that some patients seem to benefit by being exposed to strong light during the day.

The team already has future research planned to work out whether CRY1 mutations also affect the metabolism of people with DSPD, since the human circadian cycle that tells our bodies when to sleep, also regulates our hunger, metabolite and hormone levels.

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Comments

  1. Moe Moe Moe Moe United States says:

    Then, it could be years of working evenings and nights too.

    • Kathy Renbarger Kathy Renbarger United States says:

      Ever stop to consider that we work evening and nights for the same reason that "day people" work day shifts??? As a lifelong "owl," I wasn't "an owl" because I worked those shifts... I worked those shifts because "even owls need sleep." How long could you stay even remotely functional if you were forced to start working a 10~6 or 11~7 job??? How safe would you be driving to and from work???

      Something I was thinking about in between the post I wrote and deciding to do this reply might just fit nicely here: I realize that there's far more research money available for things labeled as "disorders." An alternative research funding path might be a more sociological one: While the adage of "There are only 2 types of people out and about at this hour - cops and criminals..." Is overly simplistic, it DOES  have a certain degree of merit to it. In my (never to be humble) opinion, much of that is the result of cultural stereotyping, "self-fulfilling prophesy," and reduced educational and occupational opportunities for "owls." I "was the way I was" for as far back as I can remember. Having to be in school "in the middle of my night" and usually on just a couple of hours of sleep was, at best, a major ordeal for everyone involved. My being out of phase with most people was treated as though it was behavioral; and, garnered me a LOT of flack and negative comments about both myself and my future. Fortunately, I've always been enough of a rebel to avoid internalizing it; and, intelligent enough to (essentially) "be my own teacher." While my (adoptive) parents slept, I was typically burrowed under the covers with a book, a textbook, or an encyclopedia. I half-mastered the art of "sleeping with my eyes open in school, which led to accusations of not only day-dreaming; but, even of cheating on tests. (I lost track of how many times I was forced to retake tests in the principle's office to disprove the latter!)  WAY too many "owls" I met as an adult weren't as fortunate... They bought into the assertions that they would "never amount to a hill of beans" and that there was inherently "something wrong" or "something evil" about them - which, in turn, DID divert them into criminality. I'm 64 now; and, I've often speculated "how things might have been" for not only myself; but, for so many others, if options such as 24-hour on-line schools (at every level) had been available to us. If our circadian rhythm cycles had been accepted, rather than being seen as an aberration and villainized. Personally, I could've gone MUCH further in this life; and, in my opinion, the VAST majority of those who were "washed down the drain" of criminality could, instead, have been honest, productive citizens. Many of them had become sub-consciously convinced that there was no place and no opportunities for them in this world, despite the fact that many of them could have had an enormous amount of potential. Granted, the funding from big-pharna is FAR easier to obtain; and, there actually IS a lot of resistance within "the prison industrial complex" to "maintain their cash flow;" but, I'm sure that there must be SOME person, group, etc. who'd LOVE to fund a project with the potential to not only improve individual lives; but, to reduce the tax and humanitarian burdens on our society incurs from these people seeing no future other than welfare, criminality, and a future spent in prison. NOT ALL "owls" are criminals; and, NOT ALL criminals are "owls;" but, the societal differences made by diverting even a significant number of these folks as kids into futures which included not only law enforcement; but, so many of the other fields which are opening up, which could just as easily be done at night, could be dramatically positive.  24 hour on-line college level options could transfer a significant number of menial job workers into careers which woud inspire and provide positive reinforcement for these kids. A "lark" might find it hard to believe; but, I've had conversations with quite a few truly brilliant individuals who, because of society's negative attitudes towards "owls," have been relegated to minimum wage jobs, if even that - as in the case of overnight waitresses.  Many of these who are currently stuck in jobs WAY below their potentials, with the right accommodations and certifications could excel as educator for the "owl kids," as well as excelling in other fields which are half-stocked by "larks" who HATE working night shifts and who's job performance is seriously impaired by having to work when their bodies are screaming for sleep.

      I hope everyone reading this will give it some SERIOUS thought!

  2. Kathy Renbarger Kathy Renbarger United States says:

    I have major issues with DSPS being treated as a "disorder" and labeled as "aberrant." Granted, those of us with these genetic variation ARE in the minority; HOWEVER, it's highly doubtful that a significant portion of those of you without this genetic variation would have survived into the 21st century without those of us who DO have it! While your ancestors snoozed peacefully through the night, our ancestors were the ones who insured that the fires didn't go out and your's didn't didn't become a nice dinner for predators. We had to put up with enough malignment and discrimination from "larks;" and, especially now that it's been proven to be genetic (as opposed to behavioral), we've "had it" with the [email protected] we've gotten all of our lives!!! It's ONLY a "disorder" because of the snobbery of those ancestors our ancestors protected. Granted, "we live in different times now;" but, we still have our important roles; especially in the areas of emergency services, etc. Taking it a step further, look how much we take our modern world for granted - rarely ever considering how much more devastating something such as a significant CME (not all that uncommon is our solar system's history) or an EMP attack (all too possible; especially with so many rogue states developing the technology needed for such an attack)  would be in our current world. Credible estimates of at least a 200 to 300 year technological "reset" aren't unrealistic; and, are potentially overly optimistic.

    I encourage researchers to replace the term "disorder" ("and, even "syndrome") with the term "genetic variant" and recognize the fact that it's really not all that different than genes involving skin, eye, or hair color. While we ARE a "minority," we are NOT an "aberration;" and, our genetic variations are NOT a "disorder!"

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News-Medical.Net.
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