Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome.
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.
Pubmed ID: 15800623 RIS Download
Amino Acid Sequence | Animals | Animals, Genetically Modified | Casein Kinase Idelta | Caseins | Circadian Rhythm | Darkness | Drosophila melanogaster | Female | Humans | Light | Male | Mice | Mice, Transgenic | Molecular Sequence Data | Motor Activity | Mutation, Missense | Pedigree | Phenotype | Phosvitin | Sleep Wake Disorders | Syndrome | Time Factors