title: 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.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, United States.
authors.forename: Arisa
authors.initials: A
authors.lastname: Hirano
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, United States.
authors.forename: Guangsen
authors.initials: G
authors.lastname: Shi
authors.affiliation: Department of Neurology, University of Utah, Salt Lake City, United States.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Jones
authors.affiliation: Lawrence Berkeley National Laboratory, Berkeley, United States.|Department of Energy Joint Genome Institute, Walnut Creek, United States.
authors.forename: Anna
authors.initials: A
authors.lastname: Lipzen
authors.affiliation: Lawrence Berkeley National Laboratory, Berkeley, United States.|Department of Energy Joint Genome Institute, Walnut Creek, United States.
authors.forename: Len A
authors.initials: LA
authors.lastname: Pennacchio
authors.affiliation: Center for System Biology, Soochow University, Suzhou, China.
authors.forename: Ying
authors.identifier: 0000-0002-6689-7768
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, United States.
authors.forename: William C
authors.identifier: 0000-0001-8306-8438
authors.initials: WC
authors.lastname: Hallows
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: McMahon
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, United States.
authors.forename: Maya
authors.initials: M
authors.lastname: Yamazaki
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, United States.|Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States.
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Ptáček
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, United States.
authors.forename: Ying-Hui
authors.identifier: 0000-0002-6628-0266
authors.initials: YH
authors.lastname: Fu
mesh_terms: D000409:Alanine / Q000235:genetics; D019943:Amino Acid Substitution; D000818:Animals; D056931:Cryptochromes / Q000235:genetics* / Q000378:metabolism*; D044783:F-Box Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics* / Q000378:metabolism*; D020125:Mutation, Missense; D011487:Protein Conformation; D059748:Proteolysis; D020178:Sleep Disorders, Circadian Rhythm / Q000235:genetics*; D013912:Threonine / Q000235:genetics; D054875:Ubiquitination
chemical_list: C538966:CRY2 protein, human; D056931:Cryptochromes; D044783:F-Box Proteins; C519795:FBXL3 protein, human; D050505:Mutant Proteins; D013912:Threonine; D000409:Alanine
keywords: FBXL3; Familial Advanced Sleep Phase; circadian clock; circadian rhythm; cryptochrome2; human; human biology; medicine; mouse; neuroscience