A Cryptochrome 2 Mutation Yields Advanced Sleep Phase in Human
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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Author details
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
© 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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