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By screening N-ethyl-N-nitrosourea-mutagenized animals for alterations in rhythms of wheel-running activity, we identified a mouse mutation, after hours (Afh). The mutation, a Cys(358)Ser substitution in Fbxl3, an F-box protein with leucine-rich repeats, results in long free-running rhythms of about 27 hours in homozygotes. Circadian transcriptional and translational oscillations are attenuated in Afh mice. The Afh allele significantly affected Per2 expression and delayed the rate of Cry protein degradation in Per2::Luciferase tissue slices. Our in vivo and in vitro studies reveal a central role for Fbxl3 in mammalian circadian timekeeping.

Original publication




Journal article



Publication Date





897 - 900


ARNTL Transcription Factors, Amino Acid Sequence, Amino Acid Substitution, Animals, Basic Helix-Loop-Helix Transcription Factors, CLOCK Proteins, COS Cells, Cell Cycle Proteins, Cercopithecus aethiops, Circadian Rhythm, Crosses, Genetic, Cryptochromes, F-Box Proteins, Female, Flavoproteins, Gene Expression Regulation, Liver, Lung, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C3H, Molecular Sequence Data, Nuclear Proteins, Period Circadian Proteins, Point Mutation, Suprachiasmatic Nucleus, Trans-Activators, Transcription Factors, Transcription, Genetic