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.
- 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 [email protected] [email protected].
- 5. Department of Neurology, University of California, San Francisco, CA 94143; [email protected] [email protected].
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.