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. Epub 2016 Feb 22.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Affect / physiology*
  • Aged
  • Amino Acid Sequence
  • Animals
  • Circadian Clocks / genetics
  • Female
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Middle Aged
  • Molecular Sequence Data
  • Period Circadian Proteins / genetics*
  • Period Circadian Proteins / metabolism
  • Photoperiod
  • Protein Stability
  • Seasonal Affective Disorder / genetics*
  • Sleep Disorders, Circadian Rhythm / genetics


  • PER3 protein, human
  • Per1 protein, mouse
  • Per2 protein, mouse
  • Per3 protein, mouse
  • Period Circadian Proteins