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.


  1. 1

    Jones, C. R. et al. Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans. Nature Med. 5, 1062–1065 (1999)

    CAS  Article  Google Scholar 

  2. 2

    Dunlap, J. C. Molecular bases for circadian clocks. Cell 96, 271–290 (1999)

    CAS  Article  Google Scholar 

  3. 3

    Edery, I., Zwiebel, L. J., Dembinska, M. E. & Rosbash, M. Temporal phosphorylation of the Drosophila period protein. Proc. Natl Acad. Sci. USA 91, 2260–2264 (1994)

    ADS  CAS  Article  Google Scholar 

  4. 4

    Denault, D. L., Loros, J. J. & Dunlap, J. C. WC-2 mediates WC-1–FRQ interaction within the PAS protein-linked circadian feedback loop of Neurospora. EMBO J. 20, 109–117 (2001)

    CAS  Article  Google Scholar 

  5. 5

    Young, M. W. Life's 24-hour clock: molecular control of circadian rhythms in animal cells. Trends Biochem. Sci. 25, 601–606 (2000)

    CAS  Article  Google Scholar 

  6. 6

    Lee, C., Etchegaray, J. P., Cagampang, F. R., Loudon, A. S. & Reppert, S. M. Posttranslational mechanisms regulate the mammalian circadian clock. Cell 107, 855–867 (2001)

    CAS  Article  Google Scholar 

  7. 7

    Nawathean, P. & Rosbash, M. The doubletime and CKII kinases collaborate to potentiate Drosophila PER transcriptional repressor activity. Mol. Cell 13, 213–223 (2004)

    CAS  Article  Google Scholar 

  8. 8

    Sathyanarayanan, S., Zheng, X., Xiao, R. & Sehgal, A. Posttranslational regulation of Drosophila PERIOD protein by protein phosphatase 2A. Cell 116, 603–615 (2004)

    CAS  Article  Google Scholar 

  9. 9

    Kloss, B. et al. The Drosophila clock gene double-time encodes a protein closely related to human casein kinase Iɛ. Cell 94, 97–107 (1998)

    CAS  Article  Google Scholar 

  10. 10

    Price, J. L. et al. double-time is a novel Drosophila clock gene that regulates Period protein accumulation. Cell 94, 83–95 (1998)

    CAS  Article  Google Scholar 

  11. 11

    Martinek, S., Inonog, S., Manoukian, A. S. & Young, M. W. A role for the segment polarity gene shaggy/GSK-3 in the Drosophila circadian clock. Cell 105, 769–779 (2001)

    CAS  Article  Google Scholar 

  12. 12

    Lin, J. M. et al. A role for casein kinase 2α in the Drosophila circadian clock. Nature 420, 816–820 (2002)

    ADS  CAS  Article  Google Scholar 

  13. 13

    Akten, B. et al. A role for CK2 in the Drosophila circadian oscillator. Nature Neurosci. 6, 251–257 (2003)

    CAS  Article  Google Scholar 

  14. 14

    Lowrey, P. L. et al. Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science 288, 483–492 (2000)

    ADS  CAS  Article  Google Scholar 

  15. 15

    Preuss, F. et al. Drosophila doubletime mutations which either shorten or lengthen the period of circadian rhythms decrease the protein kinase activity of casein kinase I. Mol. Cell. Biol. 24, 886–898 (2004)

    CAS  Article  Google Scholar 

  16. 16

    Beck, A. T. The Beck Depression Inventory (Harcourt Brace Jovanich, The Psychological Corporation, San Antonio, 1978)

    Google Scholar 

  17. 17

    Dahl, R. E. et al. Sleep onset abnormalities in depressed adolescents. Biol. Psychiatry 39, 400–410 (1996)

    CAS  Article  Google Scholar 

  18. 18

    Graves, P. R., Haas, D. W., Hagedorn, C. H., DePaoli-Roach, A. A. & Roach, P. J. Molecular cloning, expression, and characterization of a 49-kilodalton casein kinase I isoform from rat testis. J. Biol. Chem. 268, 6394–6401 (1993)

    CAS  PubMed  Google Scholar 

  19. 19

    Blau, J. & Young, M. W. Cycling vrille expression is required for a functional Drosophila clock. Cell 99, 661–671 (1999)

    CAS  Article  Google Scholar 

  20. 20

    Suri, V., Hall, J. C. & Rosbash, M. Two novel doubletime mutants alter circadian properties and eliminate the delay between RNA and protein in Drosophila . J. Neurosci. 20, 7547–7555 (2000)

    CAS  Article  Google Scholar 

  21. 21

    Heintz, N. BAC to the future: the use of bac transgenic mice for neuroscience research. Nature Rev. Neurosci. 2, 861–870 (2001)

    CAS  Article  Google Scholar 

  22. 22

    Ralph, M. R. & Menaker, M. A mutation of the circadian system in golden hamsters. Science 241, 1225–1227 (1988)

    ADS  CAS  Article  Google Scholar 

  23. 23

    Shearman, L. P. et al. Interacting molecular loops in the mammalian circadian clock. Science 288, 1013–1019 (2000)

    ADS  CAS  Article  Google Scholar 

  24. 24

    Lee, C., Weaver, D. R. & Reppert, S. M. Direct association between mouse PERIOD and CKIɛ is critical for a functioning circadian clock. Mol. Cell. Biol. 24, 584–594 (2004)

    CAS  Article  Google Scholar 

  25. 25

    Eide, E. J., Vielhaber, E. L., Hinz, W. A. & Virshup, D. M. The circadian regulatory proteins BMAL1 and cryptochromes are substrates of casein kinase Iɛ. J. Biol. Chem. 277, 17248–17254 (2002)

    CAS  Article  Google Scholar 

  26. 26

    Phiel, C. J. & Klein, P. S. Molecular targets of lithium action. Annu. Rev. Pharmacol. Toxicol. 41, 789–813 (2001)

    CAS  Article  Google Scholar 

  27. 27

    Gillin, J. C. The sleep therapies of depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 7, 351–364 (1983)

    CAS  Article  Google Scholar 

  28. 28

    Toh, K. L. et al. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 291, 1040–1043 (2001)

    ADS  CAS  Article  Google Scholar 

  29. 29

    Vitaterna, M. H. et al. Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. Science 264, 719–725 (1994)

    ADS  CAS  Article  Google Scholar 

  30. 30

    Antoch, M. P. et al. Functional identification of the mouse circadian Clock gene by transgenic BAC rescue. Cell 89, 655–667 (1997)

    CAS  Article  Google Scholar 

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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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