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

Luoying Zhang, Arisa Hirano, Pei Ken Hsu, Christopher R. Jones, Noriaki Sakai, Masashi Okuro, Thomas McMahon, Maya Yamazaki, Ying Xu, Noriko Saigoh, Kazumasa Saigoh, Shu Ting Lin, Krista Kaasik, Seiji Nishino, Louis J. Ptáček*, Ying Hui Fu

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

113 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)E1536-E1544
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number11
StatePublished - Mar 15 2016


  • Circadian clock
  • Circadian rhythms
  • Familial advanced sleep phase
  • PER3
  • Seasonal affective disorder

ASJC Scopus subject areas

  • General


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