Title | Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Patke A, Murphy PJ, Onat OEmre, Krieger AC, Özçelik T, Campbell SS, Young MW |
Journal | Cell |
Volume | 169 |
Issue | 2 |
Pagination | 203-215.e13 |
Date Published | 2017 04 06 |
ISSN | 1097-4172 |
Keywords | Circadian Rhythm, Cryptochromes, Exons, Female, Gene Deletion, Humans, Male, Middle Aged, Pedigree, Sleep Disorders, Circadian Rhythm |
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. |
DOI | 10.1016/j.cell.2017.03.027 |
Alternate Journal | Cell |
PubMed ID | 28388406 |
PubMed Central ID | PMC5479574 |
Grant List | 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 |