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      • Department of Molecular Biology and Genetics
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      Mutation of the human circadian clock gene CRY1 in familial delayed sleep phase disorder

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      Author(s)
      Patke, A.
      Murphy, P. J.
      Onat, O. E.
      Krieger, A. C.
      Özçelik, T.
      Campbell, S. S.
      Young, M. W.
      Date
      2017
      Source Title
      Cell
      Print ISSN
      0092-8674
      Publisher
      Cell Press
      Volume
      169
      Issue
      2
      Pages
      203 - 215
      Language
      English
      Type
      Article
      Item Usage Stats
      187
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      Abstract
      Patterns of daily human activity are controlled by an intrinsic circadian clock that promotes ∼24 hr rhythms in many behavioral and physiological processes. This system is altered in delayed sleep phase disorder (DSPD), a common form of insomnia in which sleep episodes are shifted to later times misaligned with the societal norm. Here, we report a hereditary form of DSPD associated with a dominant coding variation in the core circadian clock gene CRY1, which creates a transcriptional inhibitor with enhanced affinity for circadian activator proteins Clock and Bmal1. This gain-of-function CRY1 variant causes reduced expression of key transcriptional targets and lengthens the period of circadian molecular rhythms, providing a mechanistic link to DSPD symptoms. The allele has a frequency of up to 0.6%, and reverse phenotyping of unrelated families corroborates late and/or fragmented sleep patterns in carriers, suggesting that it affects sleep behavior in a sizeable portion of the human population. © 2017 Elsevier Inc.
      Keywords
      Circadian clock
      Circadian rhythm
      DSPD
      Sleep
      Complementary DNA
      Cryptochrome 1
      Melatonin
      Messenger RNA
      Transcription factor ARNTL
      Transcription factor CLOCK
      Permalink
      http://hdl.handle.net/11693/37425
      Published Version (Please cite this version)
      http://dx.doi.org/10.1016/j.cell.2017.03.027
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