Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome

• Published in: Nature (London) Vol. 434; no. 7033; pp. 640 - 644
• Main Authors: Xu, Ying, Padiath, Quasar S, Shapiro, Robert E, Jones, Christopher R, Wu, Susan C, Saigoh, Noriko, Saigoh, Kazumasa, Ptácek, Louis J, Fu, Ying-Hui
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 31.03.2005
• Subjects: Amino Acid Sequence; Animals; Animals, Genetically Modified; Casein Kinase Idelta - chemistry; Casein Kinase Idelta - genetics; Casein Kinase Idelta - metabolism; Caseins - metabolism; Circadian rhythm; Circadian Rhythm - genetics; Circadian Rhythm - radiation effects; Circadian rhythms; Darkness; Drosophila; Drosophila melanogaster - genetics; Drosophila melanogaster - physiology; Enzymatic activity; Female; Genetics; Humans; Insects; Light; Male; Mammals; Mice; Mice, Transgenic; Molecular Sequence Data; Motor Activity - genetics; Motor Activity - physiology; Motor Activity - radiation effects; Mutation; Mutation, Missense - genetics; Nature conservation; Pedigree; Phenotype; Phosvitin - metabolism; Sleep; Sleep Wake Disorders - genetics; Sleep Wake Disorders - physiopathology; Syndrome; Time Factors
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature03453

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.