Format

Send to

Choose Destination
Elife. 2016 Aug 16;5. pii: e16695. doi: 10.7554/eLife.16695.

A Cryptochrome 2 mutation yields advanced sleep phase in humans.

Author information

1
Department of Neurology, University of California, San Francisco, San Francisco, United States.
2
Department of Neurology, University of Utah, Salt Lake City, United States.
3
Lawrence Berkeley National Laboratory, Berkeley, United States.
4
Department of Energy Joint Genome Institute, Walnut Creek, United States.
5
Center for System Biology, Soochow University, Suzhou, China.
6
Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States.

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.

KEYWORDS:

FBXL3; Familial Advanced Sleep Phase; circadian clock; circadian rhythm; cryptochrome2; human; human biology; medicine; mouse; neuroscience

PMID:
27529127
PMCID:
PMC5398888
DOI:
10.7554/eLife.16695
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for eLife Sciences Publications, Ltd Icon for PubMed Central
Loading ...
Support Center