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Science 291 (5506): 1040-1043

Copyright © 2001 by the American Association for the Advancement of Science

An hPer2 Phosphorylation Site Mutation in Familial Advanced Sleep Phase Syndrome

Kong L. Toh,1* Christopher R. Jones,23* Yan He,4 Erik J. Eide,5 William A. Hinz,5 David M. Virshup,56 Louis J. Ptácek,27dagger Ying-Hui Fu4

Familial advanced sleep phase syndrome (FASPS) is an autosomal dominant circadian rhythm variant; affected individuals are "morning larks" with a 4-hour advance of the sleep, temperature, and melatonin rhythms. Here we report localization of the FASPS gene near the telomere of chromosome 2q. A strong candidate gene (hPer2), a human homolog of the period gene in Drosophila, maps to the same locus. Affected individuals have a serine to glycine mutation within the casein kinase Iepsilon (CKIepsilon ) binding region of hPER2, which causes hypophosphorylation by CKIepsilon in vitro. Thus, a variant in human sleep behavior can be attributed to a missense mutation in a clock component, hPER2, which alters the circadian period.

1 Department of Human Genetics,
2 Department of Neurology,
3 University Hospital Sleep Disorders Center,
4 Department of Neurobiology and Anatomy,
5 Department of Oncological Sciences and the Huntsman Cancer Institute Center for Children,
6 Department of Pediatrics,
7 Howard Hughes Medical Institute, University of Utah, Salt Lake City, UT 84112, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: ptacek{at}genetics.utah.edu

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The Orphan Nuclear Receptor Rev-erb{alpha} Recruits the N-CoR/Histone Deacetylase 3 Corepressor to Regulate the Circadian Bmal1 Gene.
L. Yin and M. A. Lazar (2005)
Mol. Endocrinol. 19, 1452-1459
   Abstract »    Full Text »    PDF »
Light-independent Phosphorylation of WHITE COLLAR-1 Regulates Its Function in the Neurospora Circadian Negative Feedback Loop.
Q. He, H. Shu, P. Cheng, S. Chen, L. Wang, and Y. Liu (2005)
J. Biol. Chem. 280, 17526-17532
   Abstract »    Full Text »    PDF »
Importin {alpha}/{beta} Mediates Nuclear Transport of a Mammalian Circadian Clock Component, mCRY2, Together with mPER2, through a Bipartite Nuclear Localization Signal.
Y. Sakakida, Y. Miyamoto, E. Nagoshi, M. Akashi, T. J. Nakamura, T. Mamine, M. Kasahara, Y. Minami, Y. Yoneda, and T. Takumi (2005)
J. Biol. Chem. 280, 13272-13278
   Abstract »    Full Text »    PDF »
Control of Mammalian Circadian Rhythm by CKI{varepsilon}-Regulated Proteasome-Mediated PER2 Degradation.
E. J. Eide, M. F. Woolf, H. Kang, P. Woolf, W. Hurst, F. Camacho, E. L. Vielhaber, A. Giovanni, and D. M. Virshup (2005)
Mol. Cell. Biol. 25, 2795-2807
   Abstract »    Full Text »    PDF »

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