title: Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome.
abstract: Familial advanced sleep phase syndrome (FASPS) is a human behavioural phenotype characterized by early sleep times and early-morning awakening. It was the first human, mendelian circadian rhythm variant to be well-characterized, and was shown to result from a mutation in a phosphorylation site within the casein kinase I (CKI)-binding domain of the human PER2 gene. To gain a deeper understanding of the mechanisms of circadian rhythm regulation in humans, we set out to identify mutations in human subjects leading to FASPS. We report here the identification of a missense mutation (T44A) in the human CKIdelta gene, which results in FASPS. This mutant kinase has decreased enzymatic activity in vitro. Transgenic Drosophila carrying the human CKIdelta-T44A gene showed a phenotype with lengthened circadian period. In contrast, transgenic mice carrying the same mutation have a shorter circadian period, a phenotype mimicking human FASPS. These results show that CKIdelta is a central component in the mammalian clock, and suggest that mammalian and fly clocks might have different regulatory mechanisms despite the highly conserved nature of their individual components.
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, California 94143-2922, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.forename: Quasar S
authors.initials: QS
authors.lastname: Padiath
authors.forename: Robert E
authors.initials: RE
authors.lastname: Shapiro
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Jones
authors.forename: Susan C
authors.initials: SC
authors.lastname: Wu
authors.forename: Noriko
authors.initials: N
authors.lastname: Saigoh
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Saigoh
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Ptácek
authors.forename: Ying-Hui
authors.initials: YH
authors.lastname: Fu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D048148:Casein Kinase Idelta / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002364:Caseins / Q000378:metabolism; D002940:Circadian Rhythm / Q000235:genetics* / Q000528:radiation effects; D003624:Darkness; D004331:Drosophila melanogaster / Q000235:genetics / Q000502:physiology; D005260:Female; D006801:Humans; D008027:Light; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009043:Motor Activity / Q000235:genetics / Q000502:physiology / Q000528:radiation effects; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D010774:Phosvitin / Q000378:metabolism; D012893:Sleep Wake Disorders / Q000235:genetics* / Q000503:physiopathology*; D013577:Syndrome; D013997:Time Factors
chemical_list: D002364:Caseins; D010774:Phosvitin; D048148:Casein Kinase Idelta