|Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder.
|Year of Publication
|Patke A, Murphy PJ, Onat OEmre, Krieger AC, Özçelik T, Campbell SS, Young MW
|2017 04 06
|Circadian Rhythm, Cryptochromes, Exons, Female, Gene Deletion, Humans, Male, Middle Aged, Pedigree, Sleep Disorders, Circadian Rhythm
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.
|PubMed Central ID
|R01 NS052495 / NS / NINDS NIH HHS / United States
R37 NS053087 / NS / NINDS NIH HHS / United States
UL1 TR000043 / TR / NCATS NIH HHS / United States
UL1 TR001866 / TR / NCATS NIH HHS / United States