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Functional consequences of a CKIdelta 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 awakening. 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 CKIdelta gene, which results in FASPS. This mutant kinase has decreased enzymatic activity in vitro. Transgenic Drosophila carrying the human CKIdelta-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 CKIdelta 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.

Pubmed ID: 15800623


  • Xu Y
  • Padiath QS
  • Shapiro RE
  • Jones CR
  • Wu SC
  • Saigoh N
  • Saigoh K
  • Pt├ícek LJ
  • Fu YH



Publication Data

March 31, 2005

Associated Grants


Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Animals, Genetically Modified
  • Casein Kinase Idelta
  • Caseins
  • Circadian Rhythm
  • Darkness
  • Drosophila melanogaster
  • Female
  • Humans
  • Light
  • Male
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Motor Activity
  • Mutation, Missense
  • Pedigree
  • Phenotype
  • Phosvitin
  • Sleep Disorders
  • Syndrome
  • Time Factors