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Functional consequences of a CKIδ 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 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 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.

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Figure 1: CKIδ-T44A FASPS pedigree and the amino acid alignment around the mutation.
Figure 2: Biochemical characterization of CKIδ-T44A.
Figure 3: Circadian locomotor activity of hCKIδ transgenic mice.

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The authors thank the FASPS subjects and their families for participating in this research. We thank U. Heberlein for advice and generous use of fly laboratory facilities, R. Threlkeld for Drosophila injections, and A. Rothenfluh for discussions and support with Drosophila transgenic lines. We also thank M. W. Young and L. Saez for the tim-UAS-gal4 stock and helpful discussions, and S. Reppert for the mouse Per1 clone. We acknowledge J. Cheung, E. Stryker and C. Whitney for technical assistance and members of the Fu and Ptáček laboratories for discussions. R.E.S. is supported by an NIH GCRC grant and the FAHC/UVM Office of Patient Oriented Research. This work was supported by an NIH grant to Y.-H.F. and L.J.P., and a Sandler Neurogenetics grant to Y.-H.F. L.J.P. is an investigator of the Howard Hughes Medical Institute.

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Correspondence to Ying-Hui Fu.

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The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Methods

This file includes additional information on the procedures that were utilized in the study. Supplementary Methods include: mutation screening and testing of controls; cloning, expression and purification of recombinant casein kinase I δ; generation of fly stocks; semi-quantitative RT-PCR for fly heads; engineering of BAC constructs for generating transgenic mice; and generation of CK1 δknock out mice. (DOC 40 kb)

Supplementary Table

This file contains Supplementary Table S1, which shows the results of period length variation from transgenic flies with normal and mutant dbt. (DOC 44 kb)

Supplementary Figure S1

This Supplementary Figure shows the actograms of transgenic flies containing the normal and mutant human CK1δ gene. (DOC 79 kb)

Supplementary Figure S2

This Supplementary Figure details the generation of human CK1δ transgenic mice. (DOC 106 kb)

Supplementary Figure 3

This Supplementary Figure details the disruption of the mouse CK1δ gene. (DOC 100 kb)

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Xu, Y., Padiath, Q., Shapiro, R. et al. Functional consequences of a CKIδ mutation causing familial advanced sleep phase syndrome. Nature 434, 640–644 (2005).

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