A PERIOD3 Variant Causes a Circadian Phenotype and is Associated with a Seasonal Mood Trait

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2016 Feb 24

PMID 26903630

Citations 72

Authors

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 Ptacek

Ying-Hui Fu

Affiliations

Soon will be listed here.

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.

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