2. Academic Validation
  3. Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder

Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder

  • Cell. 2017 Apr 6;169(2):203-215.e13. doi: 10.1016/j.cell.2017.03.027.
Alina Patke 1,  Patricia J Murphy 2,  Onur Emre Onat 3,  Ana C Krieger 4,  Tayfun Özçelik 3,  Scott S Campbell 2,  Michael W Young 5
Affiliations

Affiliations

  • 1 Laboratory of Genetics, The Rockefeller University, New York, NY 10065, USA. Electronic address: [email protected].
  • 2 Laboratory of Human Chronobiology, Weill Cornell Medical College, White Plains, NY 10605, USA.
  • 3 Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara 06800, Turkey.
  • 4 Department of Medicine, Center for Sleep Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
  • 5 Laboratory of Genetics, The Rockefeller University, New York, NY 10065, USA. Electronic address: [email protected].
PMID: 28388406 DOI: 10.1016/j.cell.2017.03.027
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.

Keywords

DSPD; circadian clock; circadian rhythm; sleep.

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