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Circadian Gene Mutation's Effect Opposite Than Thought

Mathematical modeling predicts gain-of-function, rather than loss, and has implications for drug development

THURSDAY, July 6 (HealthDay News) -- A mutation in casein kinase I (CKI), a transcription factor that regulates circadian clock genes, appears to speed up the circadian clock by increasing gene expression, rather than slowing it down as previously thought, according to a mathematical model in the July 3 Proceedings of the National Academy of Sciences Early Edition. The finding has implications for therapeutics aimed at treating jet-lag and insomnia.

Monica Gallego, Ph.D., from the University of Utah in Salt Lake City, and colleagues turned to mathematical modeling to predict the consequence of the tau mutation in CKI. The tau mutation, which shortens the circadian clock from 24 to 20 hours in hamsters, was thought to cause a loss-of-function in the CKI kinase, but that theory has been difficult to reconcile with the fact that PER1 and PER2, two circadian clock gene products affected by CKI, are degraded faster in the presence of the mutation.

The mathematical model predicted that tau is a gain-of-function mutation. The investigators verified this prediction by showing the CKI activity increases in cultured cells and that its PER substrates are degraded faster.

"Inhibitors of CKI activity have been proposed as interventions in [depression, insomnia and chronic fatigue], but predictions of drug effects have been based on the models incorporating the hypothesis that kinase loss-of-function mutations speed up the clock," the authors write. "Our data suggest that CKI inhibitors may have effects on human circadian rhythms opposite from those predicted by previous models."

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