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Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder
时间:2017/4/11 13:02:17

Patke A, Murphy PJ, Onat OE, Krieger AC, Özçelik T, Campbell SS, Young MW


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.


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


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