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Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans

Nature Medicine volume 5, pages 10621065 (1999) | Download Citation

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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 clock1,2. Autosomal semi-dominant mutations in rodents with fast or slow biological clocks (that is, short or long endogenous period lengths; τ) are associated with phase-advanced or delayed sleep–wake rhythms, respectively. These models predict the existence of familial human circadian rhythm variants3,4 but none of the human circadian rhythm disorders are known to have a familial tendency5. 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 adults6,7. Here we describe three kindreds with a profound phase advance of the sleep–wake, melatonin and temperature rhythms associated with a very short τ. 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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Acknowledgements

The authors thank A.J. Lewy, who provided discussions and comments,and A. Dean and T. Schenkenberg for critical reading of this manuscript. This investigation was supported by NIH grant HL/HD 59596 (L.J.P.) and Public Health Service research grant M01-RR00064 from the National Center for Research Resources.

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Affiliations

  1. Department of Neurology, University of Utah, Salt Lake City, Utah 84112, USA

    • Christopher R. Jones
    •  & Louis J. Ptček
  2. University Hospital Sleep Disorders Center, University of Utah, Salt Lake City, Utah 84112, USA

    • Christopher R. Jones
  3. Howard Hughes Medical Institute, University of Utah, Salt Lake City, Utah 84112, USA

    • Stephanie E. Zone
    • , Alison DeSano
    •  & Louis J. Ptček
  4. Department of Management; David Eccles School of Business, University of Utah, Salt Lake City, Utah 84112, USA

    • Fred Cooper
  5. Department of Physiology, University of Utah, Salt Lake City, Utah 84112, USA

    • Bryan Jones
  6. Department of Psychiatry, University of Utah, Salt Lake City, Utah 84112, USA

    • Laura Czajkowski
  7. Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112, USA

    • Louis J. Ptček
  8. Program in Neuroscience, University of Utah, Salt Lake City, Utah 84112, USA

    • Louis J. Ptček
  9. Department of Psychiatry, Weill Medical College of Cornell University, White Plains, New York 10605, USA

    • Scott S. Campbell
    •  & Patricia J. Murphy

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https://doi.org/10.1038/12502

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