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

• Published in: Cell Vol. 169; no. 2; pp. 203 - 215.e13
• Main Authors: Patke, Alina, Murphy, Patricia J., Onat, Onur Emre, Krieger, Ana C., Özçelik, Tayfun, Campbell, Scott S., Young, Michael W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.04.2017
• Subjects: alleles; circadian clock; Circadian Rhythm; Cryptochromes - genetics; Cryptochromes - metabolism; DSPD; Exons; Female; gain-of-function mutation; Gene Deletion; human population; Humans; Male; Middle Aged; Pedigree; phenotype; proteins; sleep; sleep disorders; Sleep Disorders, Circadian Rhythm - genetics; Sleep Disorders, Circadian Rhythm - physiopathology; transcription (genetics); sleep; DSPD; circadian clock; circadian rhythm
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2017.03.027

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. [Display omitted] •A human subject with DSPD with a variation in CRY1 has altered circadian rhythms•Proband kindred and unrelated carrier families display aberrant sleep patterns•The allele alters circadian molecular rhythms•The genetic variation enhances CRY1 function as a transcriptional inhibitor A variation in the human circadian clock gene CRY1 is associated with a familial form of delayed sleep phase disorder, providing genetic underpinnings for “night owls.”