Biological rhythms govern the ebb and flow of life on planet Earth. Animals have an internal timekeeping mechanism that precisely regulates 24-hour rhythms of body function and behavior and synchronizes them to the day/night cycle. Circadian pacemakers trigger behavioral and physiological processes that dictate our daily rhythms. Despite the importance of the circadian clock to all aspects of our physiology and behavior,the opportunity to probe the human circadian clock only recently became possible with the recognition of Mendelian circadian variants in people (familial advanced sleep phase syndrome, FASP).
We have now cloned several genes and identified mutations causing FASP. Study of these genes and the proteins they encode and engineering of the human mutations into mouse models are allowing study of this fascinating phenotype and yielding novel insights into circadian regulation in humans. Ultimately, such work will allow us to understand the similarities and differences between the human clock and those of model organisms. In addition, recent studies have also linked disruption of the circadian clock with numerous ailments, including cancer, cardiovascular diseases, asthma, and learning disorders.
Thus, studying the molecular mechanism of human circadian rhythmicity will have an enormous impact on our understanding of human health and disease. It should also lead to new strategies for pharmacological manipulation of the human clock to improve the treatment of jet lag, various clock-related sleep and psychiatric disorders, and other human diseases. (Ptacek, LJ; Jones, CR; Fu, YF. Cold Spring Harbor Symposium Quant 2007;72:273-7)
Familial Advanced Sleep Phase
Familial Advanced Sleep Phase is a circadian rhythm disorder in which sleep onset occurs in early evening and, as a consequence, wakefulness occurs in early morning.
We have isolated one gene called hPer2 that causes FASP when it occurs in a variant (mutant) form. Other genes that are transmitted in an autosomal dominant fashion are known to cause FASP in laboratory animals. We have shown that not all families with FASP have the hPer2 mutation. Therefore, mutations in other genes must also be responsible for FASP. Investigating sporadic cases of FASP will be valuable in identifying new mutations.
Familial Delayed Sleep Phase
FDSP individuals experience a delay of their sleep cycle so that they fall asleep late in the night and wake late in the morning or afternoon. FDSP is also thought to be heritable, but so far very little is known about the genetic basis of FDSP. This sleep disorder is relatively common in adolescents and often seems to resolve with age, but other individuals are affected by this condition all of their lives. While it has been difficult to fully determine the sociocultural factors that influence this sleep pattern in adolescents, it may have a strong biological basis.
Familial Natural Short Sleepers
Familial Natural Short Sleepers (FNSS) have a behavioral trait in which they have a lifelong tendency to sleep only 4 – 6 hours per night. These individuals awaken refreshed and energetic and experience this short sleep pattern even when they are on vacation and relatively free of obligations.
We have identified a mutation in a transcriptional repressor (hDEC2-P384R) that is associated with a human short sleep phenotype. Activity profiles and sleep recordings of transgenic mice carrying this mutation showed increased vigilance time and less sleep time than control mice in a zeitgeber time and sleep deprivation-dependent manner. These mice represent a model of human sleep homeostasis that provides an opportunity to probe the effect of sleep on human physical and mental health.
Advanced Sleep Phase syndrome of Aging
Advanced Sleep Phase of Aging is a profound problem for the elderly population. In fact, one third of the population over 65 years of age experience a change in their sleep cycle when they fall asleep at earlier and earlier times and then wake up early in the morning. The cause of this condition is not known but it appears in association with the normal aging process. We hypothesize that age-related changes in gene expression (rather than gene mutations) are one possible cause of the shortened sleep time for the elderly.
We’re currently testing the hypothesis that transcriptional repression of a gene (hPer2) as a stochastic process with aging causes the phenotype of earlier sleep wake times in humans.
Participate in a Research Study
We are currently enrolling participants affected by FASP, FDSP, and FNSS into our circadian studies.
Please refer to our Contact Page for more instructions.
We are currently not enrolling participants affected by ASPS of Aging. We may open enrollment in the future. If you would like to be contacted in the future for our circadian studies, please contact our clinical coordinators with your information. Please refer to the Contact Page for more information.
- TIMELESS mutation alters phase responsiveness and causes advanced sleep phase. PNAS. 2019 May 28
- Molecular Genetics of Human Sleep Behaviors. FASEB Journal. 2019 April 1
- DEC2 modulates orexin expression and regulates sleep. Proc Natl Acad Sci. 2018 March 12
- Disorders of Sleep and Circadian rhythms. Handbook Clin Neurology. 2018
- Human Genetics and Sleep Behavior. Curr Opin Neurobiol. 2017 Jun
- FAD Regulates CRYPTOCHROME Protein Stability and Circadian Clock in Mice. Cell Reports. 2017 April 11
- A Cryptochrome 2 Mutation Yields Advanced Sleep Phase in Human. Elife. 2016 Aug 16
- A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait. Proc Natl Acad Sci . 2016 Feb 22
- Genetics of human sleep behavioral phenotypes; Methods Enzymol. 2015;552:309-24 Epub 2014 Dec 26
- iBiology-Genetics of Human Circadian Rhythms and Sleep
- Nuclear envelope protein MAN1 regulates clock through BMAL1. Elife. 2014 Sep 2;3:e02981
- Glucose Sensor O-GlcNAcylation Coordinates with Phosphorylation to Regulate Circadian Clock. Cell Metab. 2013 Feb 5;17(2):291-302
- PKCγ Participates in the Entrainment of the Cerebral Circadian Clocks by Feeding. Proc Natl Acad Sci USA. 2012 Dec 11;109(50):20679-84
- The transcriptional repressor DEC2 regulates sleep length in mammals. Science 2009 325:866
- New Developments in Sleep Research: Molecular Genetics, Gene Expression, and Systems Neurobiology. J. of Neuroscience. J of Neuroscience 2008 28(46):11814-11818
- Modeling of a Human Circadian Mutation Yields Insights into Clock Regulation by PER2; Cell. 2007 Jan 12;128(1):59-70
- Functional consequences of a CKIδ mutation causing familial advanced sleep phase syndrome; Nature, Vol 434, 640-44, 31 March 2005
- An hPer2 Phosphorylation Site Mutation in Familial Advanced Sleep Phase Syndrome; Science, Vol 291, 1040-43, 9 February 2001
- Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans; Nature Medicine, Vol 5, No 9, 1062-65, September 1999
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