A Cryptochrome 2 Mutation Yields Advanced Sleep Phase in Human

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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.

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Arisa Hirano

Department of Neurology, University of California San Francisco, San Francisco, United States

Competing interests
No competing interests declared.
Guangsen Shi

Department of Neurology, University of California, San Francisco, San Francisco, United States

Competing interests
No competing interests declared.
Christopher R Jones

Department of Neurology, University of Utah, Salt Lake City, United States

Competing interests
No competing interests declared.
Anna Lipzen

Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory, Walnut Creek, United States

Competing interests
No competing interests declared.
Len A Pennacchio

DOE Joint Genome Institute, Lawrence Berkeley National Laboratory, Walnut Creek, United States

Competing interests
No competing interests declared.
Ying Xu

Center for System Biology, Soochow University, Suzhou, China

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-6689-7768
William C Hallows

Department of Neurology, University of California, San Francisco, San Francisco, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-8306-8438
Thomas McMahon

Department of Neurology, University of California, San Francisco, San Francisco, United States

Competing interests
No competing interests declared.
Maya Yamazaki

Department of Neurology, University of California, San Francisco, San Francisco, United States

Competing interests
No competing interests declared.
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.
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.

"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.

Copyright

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.