1. Neuroscience
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A Cryptochrome 2 Mutation Yields Advanced Sleep Phase in Human

  1. Arisa Hirano
  2. Guangsen Shi
  3. Christopher R Jones
  4. Anna Lipzen
  5. Len A Pennacchio
  6. Ying Xu
  7. William C Hallows
  8. Thomas McMahon
  9. Maya Yamazaki
  10. Louis J Ptáček  Is a corresponding author
  11. Ying-Hui Fu  Is a corresponding author
  1. University of California San Francisco, United States
  2. University of California, San Francisco, United States
  3. University of Utah, United States
  4. Lawrence Berkeley National Laboratory, United States
  5. Soochow University, China
Research Article
  • Cited 66
  • Views 3,187
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Cite this article as: eLife 2016;5:e16695 doi: 10.7554/eLife.16695

Abstract

Familial Advanced Sleep Phase (FASP) is a heritable human sleep phenotype characterized by very early sleep and wake times. We identified a missense mutation in the human Cryptochrome 2 (CRY2) gene that co-segregates with FASP in one family. The mutation leads to replacement of an alanine residue at position 260 with a threonine (A260T). In mice, the CRY2 mutation causes a shortened circadian period and reduced phase-shift to early-night light pulse associated with phase-advanced behavioral rhythms in the light-dark cycle. The A260T mutation is located in the phosphate loop of the flavin adenine dinucleotide (FAD) binding domain of CRY2. The mutation alters the conformation of CRY2, increasing its accessibility and affinity for FBXL3 (an E3 ubiquitin ligase), thus promoting its degradation. These results demonstrate that CRY2 stability controlled by FBXL3 plays a key role in the regulation of human sleep wake behavior.

Article and author information

Author details

  1. Arisa Hirano

    Department of Neurology, University of California San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  2. Guangsen Shi

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  3. Christopher R Jones

    Department of Neurology, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  4. Anna Lipzen

    Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory, Walnut Creek, United States
    Competing interests
    No competing interests declared.
  5. Len A Pennacchio

    DOE Joint Genome Institute, Lawrence Berkeley National Laboratory, Walnut Creek, United States
    Competing interests
    No competing interests declared.
  6. Ying Xu

    Center for System Biology, Soochow University, Suzhou, China
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6689-7768
  7. William C Hallows

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8306-8438
  8. Thomas McMahon

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  9. Maya Yamazaki

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  10. Louis J Ptáček

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    For correspondence
    ljp@ucsf.edu
    Competing interests
    Louis J Ptáček, Reviewing editor, eLife.
  11. Ying-Hui Fu

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    For correspondence
    ying-hui.fu@ucsf.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6628-0266

Funding

National Heart, Lung, and Blood Institute (HL059596)

  • Louis J Ptáček

National Institute of General Medical Sciences (GM079180)

  • Ying-Hui Fu

Japan Society for the Promotion of Science

  • Arisa Hirano

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experimental protocols (Protocol no. AN111686-02) were conducted according to US National Institutes of Health guidelines for animal research andwere approved by the Institutional Animal Care and Use Committee at the University of California, San Francisco.

Human subjects: All human subjects signed a consent form approved by the Institutional Review Boards at the University of Utah and the University of California, San Francisco (IRB# 10-03952). The consent form includes all confidentiality and ethic guidelines and also indicates not revealing subject information in the publication.

Reviewing Editor

  1. Joseph G Gleeson, Howard Hughes Medical Institute, The Rockefeller University, United States

Publication history

  1. Received: April 6, 2016
  2. Accepted: August 14, 2016
  3. Accepted Manuscript published: August 16, 2016 (version 1)
  4. Version of Record published: September 6, 2016 (version 2)
  5. Version of Record updated: September 7, 2016 (version 3)

Copyright

© 2016, Hirano et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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