title: Modeling of a human circadian mutation yields insights into clock regulation by PER2.
abstract: Circadian rhythms are endogenous oscillations of physiological and behavioral phenomena with period length of approximately 24 hr. A mutation in human Period 2 (hPER2), a gene crucial for resetting the central clock in response to light, is associated with familial advanced sleep phase syndrome (FASPS), an autosomal dominant condition with early morning awakening and early sleep times. The FASPS hPER2 S662G mutation resulted in PER2 being hypophosphorylated by casein kinase I (CKI) in vitro. We generated transgenic mice carrying the FASPS hPER2 S662G mutation and faithfully recapitulate the human phenotype. We show that phosphorylation at S662 leads to increased PER2 transcription and suggest that phosphorylation at another site leads to PER2 degradation. Altering CKIdelta dosage modulates the S662 phenotype demonstrating that CKIdelta can regulate period through PER2 in vivo. Modeling a naturally occurring human variant in mice has yielded novel insights into PER2 regulation.
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.forename: K L
authors.initials: KL
authors.lastname: Toh
authors.forename: C R
authors.initials: CR
authors.lastname: Jones
authors.forename: J-Y
authors.initials: JY
authors.lastname: Shin
authors.forename: Y-H
authors.initials: YH
authors.lastname: Fu
authors.forename: L J
authors.initials: LJ
authors.lastname: Ptácek
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001683:Biological Clocks / Q000235:genetics / Q000502:physiology*; D047389:Casein Kinase I / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002940:Circadian Rhythm / Q000502:physiology*; D005786:Gene Expression Regulation; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D056950:Period Circadian Proteins; D010641:Phenotype; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D050505:Mutant Proteins; D009687:Nuclear Proteins; C421902:PER2 protein, human; D010455:Peptides; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D018698:Glutamic Acid; D012694:Serine; D047389:Casein Kinase I