Functional consequences of a CKIδ 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, Ptáček, Louis J., Fu, Ying-Hui
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31.03.2005; Nature Publishing; Nature Publishing Group
• Subjects: Biological and medical sciences; Disorders of higher nervous function. Focal brain diseases. Central vestibular syndrome and deafness. Brain stem syndromes; Fundamental and applied biological sciences. Psychology; Humanities and Social Sciences; letter; Medical sciences; multidisciplinary; Nervous system (semeiology, syndromes); Neurology; Science; Science (multidisciplinary); Sleep. Vigilance; Vertebrates: nervous system and sense organs; Human; Nervous system diseases; Phosphorylation; Rodentia; Transgenic animal; Sleep disorder; Biological rhythm; Circadian rhythm; In vitro; Milk protein; Vertebrata; Mammalia; Missense mutation; Sleep; Enzymatic activity; Casein; Mouse; Early; Behavior; Neurological disorder
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature03453

Sleep disorders: what larks Until recently, understanding human sleep was hindered by the absence of genetic variants in human sleep patterns. But in 1999 a family was diagnosed with familial advanced sleep phase syndrome (FASPS), and work on sleep genetics was underway. Affected individuals are ‘morning larks’ or ‘early birds’, with a four-hour advance of sleep, temperature and melatonin rhythms. A mutation causing FASPS has now been identified in the casein kinase 1d gene, in a residue conserved from humans to Drosophila . In both Drosophila and mouse models the mutation causes disruption in circadian rhythms, raising the possibility that they might be useful lab models for the development of drugs to treat sleep disorders. Familial advanced sleep phase syndrome (FASPS) is a human behavioural phenotype characterized by early sleep times and early-morning awakening 1 . 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 CKIδ gene, which results in FASPS. This mutant kinase has decreased enzymatic activity in vitro . Transgenic Drosophila carrying the human CKIδ-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 CKIδ 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.