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Proc Natl Acad Sci U S A. 2019 Jun 11;116(24):12045-12053. doi: 10.1073/pnas.1819110116. Epub 2019 May 28.

TIMELESS mutation alters phase responsiveness and causes advanced sleep phase.

Author information

1
Department of Anesthesiology, University of California, San Francisco, CA 94143.
2
Department of Neurology, University of California, San Francisco, CA 94143.
3
Center for Systems Biology, Soochow University, Suzhou 215000, China.
4
Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720.
5
Department of Energy Joint Genome Institute, Walnut Creek, CA 94598.
6
Department of Neurology, University of Utah, Salt Lake City, UT 84132.
7
Department of Neurology, University of California, San Francisco, CA 94143; ying-hui.fu@ucsf.edu ljp@ucsf.edu.
8
Weill Neuroscience Institute, University of California, San Francisco, CA 94143.
9
Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, CA 94143.

Abstract

Many components of the circadian molecular clock are conserved from flies to mammals; however, the role of mammalian Timeless remains ambiguous. Here, we report a mutation in the human TIMELESS (hTIM) gene that causes familial advanced sleep phase (FASP). Tim CRISPR mutant mice exhibit FASP with altered photic entrainment but normal circadian period. We demonstrate that the mutation prevents TIM accumulation in the nucleus and has altered affinity for CRY2, leading to destabilization of PER/CRY complex and a shortened period in nonmature mouse embryonic fibroblasts (MEFs). We conclude that TIM, when excluded from the nucleus, can destabilize the negative regulators of the circadian clock, alter light entrainment, and cause FASP.

KEYWORDS:

TIMELESS; familial advanced sleep phase; human genetics; mammalian circadian clock regulation

PMID:
31138685
PMCID:
PMC6575169
[Available on 2019-11-28]
DOI:
10.1073/pnas.1819110116

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