A Cryptochrome 2 mutation yields advanced sleep phase in humans
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.
- Authors:
-
[4];
[1];
[1]
- Univ. of California, San Francisco, CA (United States). Dept. of Neurology
- Univ. of Utah, Salt Lake City, UT (United States). Dept. of Neurology
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States)
- Soochow Univ., Suzhou (China). Center for Systems Biology
- Univ. of California, San Francisco, CA (United States). Dept. of Neurology; Univ. of California, San Francisco, CA (United States). Howard Hughes Medical Inst.
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC)
- OSTI Identifier:
- 1628856
- Grant/Contract Number:
- AC02-05CH11231
- Resource Type:
- Accepted Manuscript
- Journal Name:
- eLife
- Additional Journal Information:
- Journal Volume: 5; Journal ID: ISSN 2050-084X
- Publisher:
- eLife Sciences Publications, Ltd.
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Life Sciences & Biomedicine - Other Topics
Citation Formats
Hirano, Arisa, Shi, Guangsen, Jones, Christopher R., Lipzen, Anna, Pennacchio, Len A., Xu, Ying, Hallows, William C., McMahon, Thomas, Yamazaki, Maya, Ptáček, Louis J., and Fu, Ying-Hui. A Cryptochrome 2 mutation yields advanced sleep phase in humans. United States: N. p., 2016.
Web. doi:10.7554/elife.16695.
Hirano, Arisa, Shi, Guangsen, Jones, Christopher R., Lipzen, Anna, Pennacchio, Len A., Xu, Ying, Hallows, William C., McMahon, Thomas, Yamazaki, Maya, Ptáček, Louis J., & Fu, Ying-Hui. A Cryptochrome 2 mutation yields advanced sleep phase in humans. United States. https://doi.org/10.7554/elife.16695
Hirano, Arisa, Shi, Guangsen, Jones, Christopher R., Lipzen, Anna, Pennacchio, Len A., Xu, Ying, Hallows, William C., McMahon, Thomas, Yamazaki, Maya, Ptáček, Louis J., and Fu, Ying-Hui. Sat .
"A Cryptochrome 2 mutation yields advanced sleep phase in humans". United States. https://doi.org/10.7554/elife.16695. https://www.osti.gov/servlets/purl/1628856.
@article{osti_1628856,
title = {A Cryptochrome 2 mutation yields advanced sleep phase in humans},
author = {Hirano, Arisa and Shi, Guangsen and Jones, Christopher R. and Lipzen, Anna and Pennacchio, Len A. and Xu, Ying and Hallows, William C. and McMahon, Thomas and Yamazaki, Maya and Ptáček, Louis J. and Fu, Ying-Hui},
abstractNote = {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.},
doi = {10.7554/elife.16695},
journal = {eLife},
number = ,
volume = 5,
place = {United States},
year = {Sat Apr 16 00:00:00 EDT 2016},
month = {Sat Apr 16 00:00:00 EDT 2016}
}
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Figure 1: A CRY2 mutation in FASP kindred 50035. (A) Pedigree of the family (kindred 50035) segregating the CRY2 mutation (A260T). Circles and squares represent women and men, respectively. An asterisk marks the proband. A missense mutation from G to A causes an amino acid conversion from Alanine to Threoninemore »
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