2. Academic Validation
  3. A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait

A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait

  • Proc Natl Acad Sci U S A. 2016 Mar 15;113(11):E1536-44. doi: 10.1073/pnas.1600039113.
Luoying Zhang 1,  Arisa Hirano 1,  Pei-Ken Hsu 1,  Christopher R Jones 2,  Noriaki Sakai 3,  Masashi Okuro 3,  Thomas McMahon 1,  Maya Yamazaki 1,  Ying Xu 1,  Noriko Saigoh 1,  Kazumasa Saigoh 1,  Shu-Ting Lin 1,  Krista Kaasik 1,  Seiji Nishino 3,  Louis J Ptáček 4,  Ying-Hui Fu 5
Affiliations

Affiliations

  • 1 Department of Neurology, University of California, San Francisco, CA 94143;
  • 2 Department of Neurology, University of Utah, Salt Lake City, UT 84132;
  • 3 Sleep and Circadian Neurobiology Laboratory, Stanford University, Palo Alto, CA 94304;
  • 4 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.
  • 5 Department of Neurology, University of California, San Francisco, CA 94143; ljp@ucsf.edu Ying-Hui.fu@ucsf.edu.
PMID: 26903630 DOI: 10.1073/pnas.1600039113
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.

Keywords

PER3; circadian clock; circadian rhythms; familial advanced sleep phase; seasonal affective disorder.

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