title: Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder.
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.
authors.affiliation: Laboratory of Genetics, The Rockefeller University, New York, NY 10065, USA. Electronic address: patkea@rockefeller.edu.
authors.forename: Alina
authors.initials: A
authors.lastname: Patke
authors.affiliation: Laboratory of Human Chronobiology, Weill Cornell Medical College, White Plains, NY 10605, USA.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Murphy
authors.affiliation: Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara 06800, Turkey.
authors.forename: Onur Emre
authors.initials: OE
authors.lastname: Onat
authors.affiliation: Department of Medicine, Center for Sleep Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Krieger
authors.affiliation: Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara 06800, Turkey.
authors.forename: Tayfun
authors.initials: T
authors.lastname: Özçelik
authors.affiliation: Laboratory of Human Chronobiology, Weill Cornell Medical College, White Plains, NY 10605, USA.
authors.forename: Scott S
authors.initials: SS
authors.lastname: Campbell
authors.affiliation: Laboratory of Genetics, The Rockefeller University, New York, NY 10065, USA. Electronic address: young@mail.rockefeller.edu.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Young
mesh_terms: D002940:Circadian Rhythm; D056931:Cryptochromes / Q000235:genetics / Q000378:metabolism*; D005091:Exons; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D020178:Sleep Disorders, Circadian Rhythm / Q000235:genetics* / Q000503:physiopathology
chemical_list: C538963:CRY1 protein, human; D056931:Cryptochromes
keywords: DSPD; circadian clock; circadian rhythm; sleep