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Cell. 2017 Apr 6;169(2):203-215.e13. doi: 10.1016/j.cell.2017.03.027.

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

Author information

1
Laboratory of Genetics, The Rockefeller University, New York, NY 10065, USA. Electronic address: patkea@rockefeller.edu.
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: young@mail.rockefeller.edu.

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

PMID:
28388406
PMCID:
PMC5479574
DOI:
10.1016/j.cell.2017.03.027
[Indexed for MEDLINE]
Free PMC Article

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