1. Department of Neurology, University of California, San Francisco, San Francisco, California 94143-2922, USA
2. Department of Neurology, College of Medicine, University of Vermont, Burlington, Vermont 05405, USA
3. Department of Neurology, University of Utah, Salt Lake City, Utah 84132-2305, USA
4. Howard Hughes Medical Institute, UCSF, San Francisco, California 94143-2922, USA
5. These authors contributed equally to this work
6. Present address: Department of Neurology, Kinki University School of Medicine, Osaka 589-8511, Japan

Correspondence to: Ying-Hui Fu¹ Correspondence and requests for materials should be addressed to Y.-H.F. (Email: yinghui@itsa.ucsf.edu).

Abstract

Familial advanced sleep phase syndrome (FASPS) is a human behavioural phenotype characterized by early sleep times and early-morning awakening¹. 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 CKI gene, which results in FASPS. This mutant kinase has decreased enzymatic activity in vitro. Transgenic Drosophila carrying the human CKI-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 CKI 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.

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