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

TitleMutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder.
Publication TypeJournal Article
Year of Publication2017
AuthorsPatke A, Murphy PJ, Onat OEmre, Krieger AC, Özçelik T, Campbell SS, Young MW
JournalCell
Volume169
Issue2
Pagination203-215.e13
Date Published2017 04 06
ISSN1097-4172
KeywordsCircadian 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.

DOI10.1016/j.cell.2017.03.027
Alternate JournalCell
PubMed ID28388406
PubMed Central IDPMC5479574
Grant ListR01 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

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