title: A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait.
abstract: In humans, the connection between sleep and mood has long been recognized, although direct molecular evidence is lacking. We identified two rare variants in the circadian clock gene PERIOD3 (PER3-P415A/H417R) in humans with familial advanced sleep phase accompanied by higher Beck Depression Inventory and seasonality scores. hPER3-P415A/H417R transgenic mice showed an altered circadian period under constant light and exhibited phase shifts of the sleep-wake cycle in a short light period (photoperiod) paradigm. Molecular characterization revealed that the rare variants destabilized PER3 and failed to stabilize PERIOD1/2 proteins, which play critical roles in circadian timing. Although hPER3-P415A/H417R-Tg mice showed a mild depression-like phenotype, Per3 knockout mice demonstrated consistent depression-like behavior, particularly when studied under a short photoperiod, supporting a possible role for PER3 in mood regulation. These findings suggest that PER3 may be a nexus for sleep and mood regulation while fine-tuning these processes to adapt to seasonal changes.
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143;
authors.forename: Luoying
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143;
authors.forename: Arisa
authors.initials: A
authors.lastname: Hirano
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143;
authors.forename: Pei-Ken
authors.initials: PK
authors.lastname: Hsu
authors.affiliation: Department of Neurology, University of Utah, Salt Lake City, UT 84132;
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Jones
authors.affiliation: Sleep and Circadian Neurobiology Laboratory, Stanford University, Palo Alto, CA 94304;
authors.forename: Noriaki
authors.initials: N
authors.lastname: Sakai
authors.affiliation: Sleep and Circadian Neurobiology Laboratory, Stanford University, Palo Alto, CA 94304;
authors.forename: Masashi
authors.initials: M
authors.lastname: Okuro
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143;
authors.forename: Thomas
authors.initials: T
authors.lastname: McMahon
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143;
authors.forename: Maya
authors.initials: M
authors.lastname: Yamazaki
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143;
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143;
authors.forename: Noriko
authors.initials: N
authors.lastname: Saigoh
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143;
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Saigoh
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143;
authors.forename: Shu-Ting
authors.initials: ST
authors.lastname: Lin
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143;
authors.forename: Krista
authors.initials: K
authors.lastname: Kaasik
authors.affiliation: Sleep and Circadian Neurobiology Laboratory, Stanford University, Palo Alto, CA 94304;
authors.forename: Seiji
authors.initials: S
authors.lastname: Nishino
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143; Howard Hughes Medical Institute, University of California, San Francisco, CA 94143 ljp@ucsf.edu Ying-Hui.fu@ucsf.edu.
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Ptáček
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143; ljp@ucsf.edu Ying-Hui.fu@ucsf.edu.
authors.forename: Ying-Hui
authors.initials: YH
authors.lastname: Fu
mesh_terms: D000339:Affect / Q000502:physiology*; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D057906:Circadian Clocks / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D008969:Molecular Sequence Data; D056950:Period Circadian Proteins / Q000235:genetics* / Q000378:metabolism; D017440:Photoperiod; D055550:Protein Stability; D016574:Seasonal Affective Disorder / Q000235:genetics*; D020178:Sleep Disorders, Circadian Rhythm / Q000235:genetics
chemical_list: C512644:PER3 protein, human; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; C512645:Per3 protein, mouse; D056950:Period Circadian Proteins
keywords: PER3; circadian clock; circadian rhythms; familial advanced sleep phase; seasonal affective disorder