Familial advanced sleep-phase syndrome: a short-period circadian rhythm variant in humans
Abstract
Biological circadian clocks oscillate with an approximately 24-hour period, are ubiquitous, and presumably confer a selective advantage by anticipating the transitions between day and night. The circadian rhythms of sleep, melatonin secretion and body core temperature are thought to be generated by the suprachiasmatic nucleus of the hypothalamus, the anatomic locus of the mammalian circadian clock. Autosomal semi-dominant mutations in rodents with fast or slow biological clocks (that is, short or long endogenous period lengths; tau) are associated with phase-advanced or delayed sleep-wake rhythms, respectively. These models predict the existence of familial human circadian rhythm variants but none of the human circadian rhythm disorders are known to have a familial tendency. Although a slight 'morning lark' tendency is common, individuals with a large and disabling sleep phase-advance are rare. This disorder, advanced sleep-phase syndrome, is characterized by very early sleep onset and offset; only two cases are reported in young adults. Here we describe three kindreds with a profound phase advance of the sleep-wake, melatonin and temperature rhythms associated with a very short tau. The trait segregates as an autosomal dominant with high penetrance. These kindreds represent a well-characterized familial circadian rhythm variant in humans and provide a unique opportunity for genetic analysis of human circadian physiology.
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Rare cases of familial extreme chronotype disorders, such as advanced sleep-phase syndrome, have been described.
“Concerning the influence of nonmodifiable determinants, rare cases of familial extreme chronotype disorders, such as advanced sleep-phase syndrome, have been described (36, 37).”
From Chronotype: Implications for Epidemiologic Studies on Chrono-Nutrition and Cardiometabolic Health (2019) · cites this paper as [37]
Cites
Rechtschaffen, A. (1968) · Medical Entomology and Zoology · Cited by 11,772 · see citing works
A self-assessment questionnaire to determine morningness- eveningness in human circadian rhythms
Home, J. K. (1976) · Medical Entomology and Zoology · Cited by 4,783 · see citing works
Mutagenesis and Mapping of a Mouse Gene, <i>Clock</i> , Essential for Circadian Behavior
Vitaterna, M. H., King, D. P., Chang, A.-M., Kornhauser, J. M., Lowrey, P. L., McDonald, J. D., Dove, W. F., Pinto, L. H., Turek, F. W., & Takahashi, J. S. (1994) · Science · doi:10.1126/science.8171325 · Cited by 1,632 · see citing works
Guidelines for the Multiple Sleep Latency Test (MSLT): A Standard Measure of Sleepiness
Carskadon, M. A. (1986) · SLEEP · doi:10.1093/sleep/9.4.519 · Cited by 1,607 · see citing works
Human Sleep: Its Duration and Organization Depend on Its Circadian Phase
Czeisler, C. A., Weitzman, E. D., Moore-Ede, M. C., Zimmerman, J. C., & Knauer, R. S. (1980) · Science · doi:10.1126/science.7434029 · Cited by 903 · see citing works
Closing the Circadian Loop: CLOCK-Induced Transcription of Its Own Inhibitors per and tim
Darlington, T. K., Wager‐Smith, K., Ceriani, M. F., Staknis, D., Gekakis, N., Steeves, T. D. L., Weitz, C. J., Takahashi, J. S., & Kay, S. A. (1998) · Science · doi:10.1126/science.280.5369.1599 · Cited by 826 · see citing works
A Mutation of the Circadian System in Golden Hamsters
Ralph, M. R., & Menaker, M. (1988) · Science · doi:10.1126/science.3413487 · Cited by 700 · see citing works
A CLOCK Polymorphism Associated with Human Diurnal Preference
Katzenberg, D. R., Young, T. B., Finn, L. A., Lin, L., King, D. P., Takahashi, J. S., & Mignot, E. J.-M. (1998) · SLEEP · doi:10.1093/sleep/21.6.569 · Cited by 587 · see citing works
Ultrashort sleep-waking schedule. III. ‘Gates’ and ‘Forbidden zones’ for sleep
Lavie, P. (1986) · Electroencephalography and Clinical Neurophysiology · doi:10.1016/0013-4694(86)90123-9 · Cited by 480 · see citing works
The Dim Light Melatonin Onset as a Marker for Orcadian Phase Position
Lewy, A. J., & Sack, R. L. (1989) · Chronobiology International · doi:10.3109/07420528909059144 · Cited by 418 · see citing works
Shanahan, T. L., & Czeisler, C. A. (1991) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-73-2-227 · Cited by 217 · see citing works
Sleep studies on a 90-minute day
Carskadon, M. A., & Dement, W. C. (1975) · Electroencephalography and Clinical Neurophysiology · doi:10.1016/0013-4694(75)90004-8 · Cited by 194 · see citing works
Klerman, E., Dijk, D., Kronauer, R. E., & Czeisler, C. A. (1996) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1996.270.1.r271 · Cited by 120 · see citing works
Ss, C., Gillin, J. C., Kripke, D. F., Erikson, P., & Clopton, P. (1989) · PubMed · Cited by 120 · see citing works
Long-term stability and psychometric properties of the CompositeScale of Morningness
Greenwood, K. M. (1994) · Ergonomics · doi:10.1080/00140139408963653 · Cited by 100 · see citing works
Chokroverty, S. (2017) · Springer eBooks · doi:10.1007/978-1-4939-6578-6 · Cited by 84 · see citing works
When the Human Circadian System is Caught Napping: Evidence for Endogenous Rhythms Close to 24 Hours
Campbell, S. S., Dawson, D. E., & Zulley, J. (1993) · SLEEP · doi:10.1093/sleep/16.7.638 · Cited by 77 · see citing works
Self-citationHaimov, I., & Lavie, P. (1997) · SLEEP · doi:10.1093/sleep/20.4.294 · Cited by 76 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Life between Clocks: Daily Temporal Patterns of Human Chronotypes
Roenneberg, T., Wirz-Justice, A., & Merrow, M. (2003) · Journal of Biological Rhythms · doi:10.1177/0748730402239679 · Cited by 2,662 · see citing works
The genetics of mammalian circadian order and disorder: implications for physiology and disease
Takahashi, J. S., Hong, H.-K., Ko, C. H., & McDearmon, E. L. (2008) · Nature Reviews Genetics · doi:10.1038/nrg2430 · Cited by 1,611 · see citing works
Epidemiology of the human circadian clock
Roenneberg, T., Kuehnle, T., Juda, M., Kantermann, T., Allebrandt, K., Gordijn, M., & Merrow, M. (2007) · Sleep Medicine Reviews · doi:10.1016/j.smrv.2007.07.005 · Cited by 1,545 · see citing works
An h <i>Per2</i> Phosphorylation Site Mutation in Familial Advanced Sleep Phase Syndrome
Toh, K. L., Jones, C. R., He, Y., Eide, E. J., Hinz, W. A., Virshup, D. M., Ptáček, L. J., & Fu, Y.-H. (2001) · Science · doi:10.1126/science.1057499 · Cited by 1,460 · see citing works
Mammalian circadian biology: elucidating genome-wide levels of temporal organization
Lowrey, P. L., & Takahashi, J. S. (2004) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.5.061903.175925 · Cited by 976 · see citing works
Functional consequences of a CKIδ mutation causing familial advanced sleep phase syndrome
Xu, Y., Padiath, Q. S., Shapiro, R. E., Jones, C. R., Wu, S. C., Saigoh, N., Saigoh, K., Ptáček, L. J., & Fu, Y.-H. (2005) · Nature · doi:10.1038/nature03453 · Cited by 861 · see citing works
Self-citationPractice Parameters for the Clinical Evaluation and Treatment of Circadian Rhythm Sleep Disorders
Morgenthaler, T. I., Lee-Chiong, T., Alessi, C., Friedman, L., Aurora, R. N., Boehlecke, B., Brown, T., Chesson, A. L., Kapur, V., Maganti, R., et al. (2007) · Sleep · doi:10.1093/sleep/30.11.1445 · Cited by 629 · see citing works
REM sleep dysregulation in depression: state of the art
Palagini, L., Baglioni, C., Ciapparelli, A., Gemignani, A., & Riemann, D. (2013) · Sleep Medicine Reviews · doi:10.1016/j.smrv.2012.11.001 · Cited by 513 · see citing works
Duffy, J. F., Rimmer, D. W., & Czeisler, C. A. (2001) · Behavioral Neuroscience · doi:10.1037/0735-7044.115.4.895 · Cited by 571 · see citing works
Evidence‐Based Recommendations for the Assessment and Management of Sleep Disorders in Older Persons
Bloom, H. G., Ahmed, I., Alessi, C. A., Ancoli‐Israel, S., Buysse, D. J., Kryger, M. H., Phillips, B. A., Thorpy, M. J., Vitiello, M. V., & Zee, P. C. (2009) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.2009.02220.x · Cited by 464 · see citing works
Circadian rhythms, sleep deprivation, and human performance
Goel, N., Basner, M., Rao, H., & Dinges, D. F. (2013) · Progress in Molecular Biology and Translational Science · doi:10.1016/b978-0-12-396971-2.00007-5 · Cited by 400 · see citing works
“, <24 h).(159) In one study, ASPD was shown to be associated with a mutation in PER2,(160) although a later study failed to replicate this finding.”
Paine, S.-J., Gander, P. H., & Travier, N. (2006) · Journal of Biological Rhythms · doi:10.1177/0748730405283154 · Cited by 377 · see citing works
Circadian rhythms and disorders of the timing of sleep
Meyer, N., Harvey, A. G., Lockley, S. W., & Dijk, D.-J. (2022) · The Lancet · doi:10.1016/s0140-6736(22)00877-7 · Cited by 346 · see citing works
Sex differences in circadian timing systems: implications for disease
Bailey, M., & Silver, R. (2014) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2013.11.003 · Cited by 348 · see citing works
Lane, J. M., Vlasac, I., Anderson, S. G., Kyle, S. D., Dixon, W. G., Bechtold, D. A., Gill, S., Little, M. A., Luik, A., Loudon, A., et al. (2016) · Nature Communications · doi:10.1038/ncomms10889 · Cited by 312 · see citing works
The relationship between insomnia and body temperatures
Lack, L. C., Gradisar, M., Van Someren, E. J. W., Wright, H. R., & Lushington, K. (2008) · Sleep Medicine Reviews · doi:10.1016/j.smrv.2008.02.003 · Cited by 285 · see citing works
Unearthing the phylogenetic roots of sleep
Allada, R., & Siegel, J. M. (2008) · Current Biology · doi:10.1016/j.cub.2008.06.033 · Cited by 280 · see citing works
Molecular insights into human daily behavior
Brown, S. A., Kunz, D., Dumas, A., Westermark, P. O., Vanselow, K., Tilmann-Wahnschaffe, A., Herzel, H., & Kramer, A. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0707772105 · Cited by 270 · see citing works
Endophenotypes in bipolar disorder
Lenox, R. H., Gould, T. D., & Manji, H. K. (2002) · American Journal of Medical Genetics · doi:10.1002/ajmg.10360 · Cited by 264 · see citing works
Genetic basis of chronotype in humans: insights from three landmark GWAS
Kalmbach, D. A., Schneider, L. D., Cheung, J., Bertrand, S. J., Kariharan, T., Pack, A. I., & Gehrman, P. R. (2017) · Sleep · doi:10.1093/sleep/zsw048 · Cited by 243 · see citing works
Chronotype: Implications for Epidemiologic Studies on Chrono-Nutrition and Cardiometabolic Health
Almoosawi, S., Vingeliene, S., Gachon, F., Voortman, T., Palla, L., Johnston, J. D., Van Dam, R. M., Darimont, C., & Karagounis, L. G. (2019) · Advances in Nutrition · doi:10.1093/advances/nmy070 · Cited by 247 · see citing works
Genetics of circadian rhythms and sleep in human health and disease
Lane, J. M., Qian, J., Mignot, E., Redline, S., Scheer, F. A. J. L., & Saxena, R. (2023) · Nature Reviews Genetics · doi:10.1038/s41576-022-00519-z · Cited by 236 · see citing works
A clinical approach to circadian rhythm sleep disorders
Barion, A., & Zee, P. C. (2007) · Sleep Medicine · doi:10.1016/j.sleep.2006.11.017 · Cited by 214 · see citing works
Human blood metabolite timetable indicates internal body time
Kasukawa, T., Sugimoto, M., Hida, A., Minami, Y., Mori, M., Honma, S., Honma, K.-I., Mishima, K., Soga, T., & Ueda, H. R. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1207768109 · Cited by 211 · see citing works
Bunney, B. G., & Bunney, W. E. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.07.020 · Cited by 181 · see citing works
Selective Inhibition of Casein Kinase 1ϵ Minimally Alters Circadian Clock Period
Walton, K. M., Fisher, K., Rubitski, D., Marconi, M., Meng, Q.-J., Sládek, M., Adams, J., Bass, M., Chandrasekaran, R., Butler, T., et al. (2009) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.109.151415 · Cited by 184 · see citing works
A <i>PERIOD3</i> variant causes a circadian phenotype and is associated with a seasonal mood trait
Zhang, L., Hirano, A., Hsu, P.-K., Jones, C. R., Sakai, N., Okuro, M., McMahon, T., Yamazaki, M., Xu, Y., Saigoh, N., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1600039113 · Cited by 169 · see citing works
Self-citationArble, D. M., Bass, J., Behn, C. D., Butler, M. P., Challet, E., Czeisler, C., Depner, C. M., Elmquist, J., Franken, P., Grandner, M. A., et al. (2015) · Sleep · doi:10.5665/sleep.5226 · Cited by 173 · see citing works
Self-citationPlasticity of the Intrinsic Period of the Human Circadian Timing System
Scheer, F. A. J. L., Wright, K. P., Kronauer, R. E., & Czeisler, C. A. (2007) · PLoS ONE · doi:10.1371/journal.pone.0000721 · Cited by 146 · see citing works
Genetics of the human circadian clock and sleep homeostat
Ashbrook, L. H., Krystal, A. D., Fu, Y.-H., & Ptáček, L. J. (2020) · Neuropsychopharmacology · doi:10.1038/s41386-019-0476-7 · Cited by 123 · see citing works
Self-citationKuhlman, S. J., Craig, L. M., & Duffy, J. F. (2018) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a033613 · Cited by 107 · see citing works
Chronobiology and mood disorders
Wirz-Justice, A. (2003) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2003.5.4/awirzjustice · Cited by 91 · see citing works
Phenotypic effects of genetic variability in human clock genes on circadian and sleep parameters
Von Schantz, M. (2008) · Journal of Genetics · doi:10.1007/s12041-008-0074-7 · Cited by 85 · see citing works
The search for circadian clock components in humans: new perspectives for association studies
Allebrandt, K. V., & Roenneberg, T. (2008) · Brazilian Journal of Medical and Biological Research · doi:10.1590/s0100-879x2008000800013 · Cited by 84 · see citing works
von Schantz, M., Taporoski, T. P., Horimoto, A. R. V. R., Duarte, N. E., Vallada, H., Krieger, J. E., Pedrazzoli, M., Negrão, A. B., & Pereira, A. C. (2015) · Scientific Reports · doi:10.1038/srep09214 · Cited by 80 · see citing works
Treating chronobiological components of chronic insomnia
Lack, L. C., & Wright, H. R. (2007) · Sleep Medicine · doi:10.1016/j.sleep.2006.10.003 · Cited by 74 · see citing works
Hasan, S., Santhi, N., Lazar, A. S., Slak, A., Lo, J., von Schantz, M., Archer, S. N., Johnston, J. D., & Dijk, D. (2012) · The FASEB Journal · doi:10.1096/fj.11-201699 · Cited by 68 · see citing works
Genetics of Human Sleep Behavioral Phenotypes
Hsu, P.-K., Ptáček, L. J., & Fu, Y.-H. (2015) · Methods in Enzymology · doi:10.1016/bs.mie.2014.10.046 · Cited by 29 · see citing works
Self-citationMutation screening of the human period 2 gene in bipolar disorder
Shiino, Y., Nakajima, S., Ozeki, Y., Isono, T., & Yamada, N. (2003) · Neuroscience Letters · doi:10.1016/s0304-3940(02)01290-9 · Cited by 30 · see citing works
Genetics of sleep timing, duration and homeostasis in humans
Goel, N. (2011) · Sleep Medicine Clinics · doi:10.1016/j.jsmc.2011.03.004 · Cited by 27 · see citing works
- Authors
- Jones, C. R., Campbell, S. S., Zone, S. E., Cooper, F., DeSano, A., Murphy, P. J., Jones, B., Czajkowski, L., & Ptček, L. J.
- Affiliations
- University of Utah (US)
- Cornell University (US)
- Howard Hughes Medical Institute (US)
- Venue
- Nature Medicine
- Published
- 1999-09
- Volume
- 5
- Issue
- 9
- Pages
- 1062-1065
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W1557411044
- Cited by
- 567
- References
- 18
- Citations by year
- 2026: 6 · 2025: 13 · 2024: 11 · 2023: 10 · 2022: 25 · 2021: 19 · 2020: 18 · 2019: 20 · 2018: 15 · 2017: 18 · 2016: 20 · 2015: 23 · 2014: 26 · 2013: 37 · 2012: 29
- FWCI
- 5.55
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL/HD 59596)
- National Center for Research Resources (M01-RR 00064, M01RR000064)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and Work-Related Fatigue
- Keywords
- advanced sleep phase syndrome, circadian clock, circadian period, autosomal dominant inheritance, melatonin rhythm, sleep-wake cycle, suprachiasmatic nucleus, kindred
- MeSH terms
- Activity Cycles, Adult, Aged, Child, Circadian Rhythm, Europe, Family Health, Female, Genes, Dominant, Humans, Male, Melatonin, Middle Aged, Pedigree, Sleep, Sleep Wake Disorders, Sleep Stages, Temperature, Time Factors, Genetic Variation, Matched-Pair Analysis, Polysomnography, Penetrance
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