Skip to main content
  • Submit
  • About
    • Editorial Board
    • PNAS Staff
    • FAQ
    • Accessibility Statement
    • Rights and Permissions
    • Site Map
  • Contact
  • Journal Club
  • Subscribe
    • Subscription Rates
    • Subscriptions FAQ
    • Open Access
    • Recommend PNAS to Your Librarian
  • Log in
  • My Cart

Main menu

  • Home
  • Articles
    • Current
    • Special Feature Articles - Most Recent
    • Special Features
    • Colloquia
    • Collected Articles
    • PNAS Classics
    • List of Issues
  • Front Matter
  • News
    • For the Press
    • This Week In PNAS
    • PNAS in the News
  • Podcasts
  • Authors
    • Information for Authors
    • Editorial and Journal Policies
    • Submission Procedures
    • Fees and Licenses
  • Submit
  • About
    • Editorial Board
    • PNAS Staff
    • FAQ
    • Accessibility Statement
    • Rights and Permissions
    • Site Map
  • Contact
  • Journal Club
  • Subscribe
    • Subscription Rates
    • Subscriptions FAQ
    • Open Access
    • Recommend PNAS to Your Librarian

User menu

  • Log in
  • My Cart

Search

  • Advanced search
Home
Home

Advanced Search

  • Home
  • Articles
    • Current
    • Special Feature Articles - Most Recent
    • Special Features
    • Colloquia
    • Collected Articles
    • PNAS Classics
    • List of Issues
  • Front Matter
  • News
    • For the Press
    • This Week In PNAS
    • PNAS in the News
  • Podcasts
  • Authors
    • Information for Authors
    • Editorial and Journal Policies
    • Submission Procedures
    • Fees and Licenses

New Research In

Physical Sciences

Featured Portals

  • Physics
  • Chemistry
  • Sustainability Science

Articles by Topic

  • Applied Mathematics
  • Applied Physical Sciences
  • Astronomy
  • Computer Sciences
  • Earth, Atmospheric, and Planetary Sciences
  • Engineering
  • Environmental Sciences
  • Mathematics
  • Statistics

Social Sciences

Featured Portals

  • Anthropology
  • Sustainability Science

Articles by Topic

  • Economic Sciences
  • Environmental Sciences
  • Political Sciences
  • Psychological and Cognitive Sciences
  • Social Sciences

Biological Sciences

Featured Portals

  • Sustainability Science

Articles by Topic

  • Agricultural Sciences
  • Anthropology
  • Applied Biological Sciences
  • Biochemistry
  • Biophysics and Computational Biology
  • Cell Biology
  • Developmental Biology
  • Ecology
  • Environmental Sciences
  • Evolution
  • Genetics
  • Immunology and Inflammation
  • Medical Sciences
  • Microbiology
  • Neuroscience
  • Pharmacology
  • Physiology
  • Plant Biology
  • Population Biology
  • Psychological and Cognitive Sciences
  • Sustainability Science
  • Systems Biology
Research Article

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, and Ying-Hui Fu
PNAS first published February 22, 2016; https://doi.org/10.1073/pnas.1600039113
Luoying Zhang
aDepartment of Neurology, University of California, San Francisco, CA 94143;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Arisa Hirano
aDepartment of Neurology, University of California, San Francisco, CA 94143;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Pei-Ken Hsu
aDepartment of Neurology, University of California, San Francisco, CA 94143;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christopher R. Jones
bDepartment of Neurology, University of Utah, Salt Lake City, UT 84132;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Noriaki Sakai
cSleep and Circadian Neurobiology Laboratory, Stanford University, Palo Alto, CA 94304;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Masashi Okuro
cSleep and Circadian Neurobiology Laboratory, Stanford University, Palo Alto, CA 94304;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Thomas McMahon
aDepartment of Neurology, University of California, San Francisco, CA 94143;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Maya Yamazaki
aDepartment of Neurology, University of California, San Francisco, CA 94143;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ying Xu
aDepartment of Neurology, University of California, San Francisco, CA 94143;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Noriko Saigoh
aDepartment of Neurology, University of California, San Francisco, CA 94143;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kazumasa Saigoh
aDepartment of Neurology, University of California, San Francisco, CA 94143;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shu-Ting Lin
aDepartment of Neurology, University of California, San Francisco, CA 94143;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Krista Kaasik
aDepartment of Neurology, University of California, San Francisco, CA 94143;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Seiji Nishino
cSleep and Circadian Neurobiology Laboratory, Stanford University, Palo Alto, CA 94304;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Louis J. Ptáček
aDepartment of Neurology, University of California, San Francisco, CA 94143;
dHoward Hughes Medical Institute, University of California, San Francisco, CA 94143
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: ljp@ucsf.edu Ying-Hui.fu@ucsf.edu
Ying-Hui Fu
aDepartment of Neurology, University of California, San Francisco, CA 94143;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: ljp@ucsf.edu Ying-Hui.fu@ucsf.edu
  1. Contributed by Louis J. Ptáček, January 4, 2016 (sent for review October 5, 2015; reviewed by Nelson B. Freimer, Daniel H. Geschwind, and Emmanuel J. M. Mignot)

  • Article
  • Figures & SI
  • Info & Metrics
  • PDF
Loading

Significance

It has long been thought that sleep and mood are intimately connected in humans, but at present there are no known molecular links. We identified rare variants in the PERIOD3 gene in persons with both altered sleep behavior and features of seasonal affective disorder. We show that these variants recapitulate circadian and mood phenotypes in mouse models. Although we were not able to test mood in fruit flies, we did uncover a sleep trait similar to that seen in humans in flies carrying the human variants. Our molecular studies reveal that the variants led to less stable PER3 protein and reduced the stabilizing effect of PER3 on PER1/PER2, providing a mechanistic explanation for the circadian trait.

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.

  • circadian clock
  • circadian rhythms
  • familial advanced sleep phase
  • seasonal affective disorder
  • PER3

Footnotes

  • ↵1L.Z. and A.H. contributed equally to this work.

  • ↵2Present address: Faculty of Medicine, Department of Neurology, Kinki University, 577-8502 Osaka, Japan.

  • ↵3To whom correspondence may be addressed. Email: ljp{at}ucsf.edu or Ying-Hui.fu{at}ucsf.edu.
  • Author contributions: L.Z., L.J.P., and Y.-H.F. designed research; L.Z., A.H., P.-K.H., C.R.J., N. Sakai, M.O., T.M., M.Y., N. Saigoh, K.S., S.-T.L., and K.K. performed research; Y.X. and S.N. contributed new reagents/analytic tools; L.Z., A.H., P.-K.H., C.R.J., N. Sakai, and M.O. analyzed data; and L.Z., A.H., L.J.P., and Y.-H.F. wrote the paper.

  • Reviewers: N.B.F., UCLA Center for Neurobehavioral Genetics; D.H.G., University of California Los Angeles; and E.J.M.M., Stanford University School of Medicine.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1600039113/-/DCSupplemental.

http://www.pnas.org/preview_site/misc/userlicense.xhtml

View Full Text
Next
Back to top
Article Alerts
Email Article

Thank you for your interest in spreading the word on PNAS.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait
(Your Name) has sent you a message from PNAS
(Your Name) thought you would like to see the PNAS web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
PERIOD3 contributes to sleep and mood
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
Proceedings of the National Academy of Sciences Feb 2016, 201600039; DOI: 10.1073/pnas.1600039113

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
PERIOD3 contributes to sleep and mood
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
Proceedings of the National Academy of Sciences Feb 2016, 201600039; DOI: 10.1073/pnas.1600039113
Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Mendeley logo Mendeley
Proceedings of the National Academy of Sciences: 118 (9)
Current Issue

Submit

Sign up for Article Alerts

Jump to section

  • Article
    • Abstract
    • Results
    • Discussion
    • Materials and Methods
    • SI Materials and Methods
    • Acknowledgments
    • Footnotes
    • References
  • Figures & SI
  • Info & Metrics
  • PDF

You May Also be Interested in

Surgeons hands during surgery
Inner Workings: Advances in infectious disease treatment promise to expand the pool of donor organs
Despite myriad challenges, clinicians see room for progress.
Image credit: Shutterstock/David Tadevosian.
Setting sun over a sun-baked dirt landscape
Core Concept: Popular integrated assessment climate policy models have key caveats
Better explicating the strengths and shortcomings of these models will help refine projections and improve transparency in the years ahead.
Image credit: Witsawat.S.
Double helix
Journal Club: Noncoding DNA shown to underlie function, cause limb malformations
Using CRISPR, researchers showed that a region some used to label “junk DNA” has a major role in a rare genetic disorder.
Image credit: Nathan Devery.
Steamboat Geyser eruption.
Eruption of Steamboat Geyser
Mara Reed and Michael Manga explore why Yellowstone's Steamboat Geyser resumed erupting in 2018.
Listen
Past PodcastsSubscribe
Birds nestling on tree branches
Parent–offspring conflict in songbird fledging
Some songbird parents might improve their own fitness by manipulating their offspring into leaving the nest early, at the cost of fledgling survival, a study finds.
Image credit: Gil Eckrich (photographer).

Similar Articles

Site Logo
Powered by HighWire
  • Submit Manuscript
  • Twitter
  • Facebook
  • RSS Feeds
  • Email Alerts

Articles

  • Current Issue
  • Special Feature Articles – Most Recent
  • List of Issues

PNAS Portals

  • Anthropology
  • Chemistry
  • Classics
  • Front Matter
  • Physics
  • Sustainability Science
  • Teaching Resources

Information

  • Authors
  • Editorial Board
  • Reviewers
  • Librarians
  • Press
  • Site Map
  • PNAS Updates

Feedback    Privacy/Legal

Copyright © 2021 National Academy of Sciences. Online ISSN 1091-6490