Functional Consequences of a CKIdelta Mutation Causing Familial Advanced Sleep Phase Syndrome

Nature. 2005 Mar 31;434(7033):640-4. doi: 10.1038/nature03453.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Animals, Genetically Modified
  • Casein Kinase Idelta / chemistry
  • Casein Kinase Idelta / genetics*
  • Casein Kinase Idelta / metabolism
  • Caseins / metabolism
  • Circadian Rhythm / genetics*
  • Circadian Rhythm / radiation effects
  • Darkness
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / physiology
  • Female
  • Humans
  • Light
  • Male
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Motor Activity / genetics
  • Motor Activity / physiology
  • Motor Activity / radiation effects
  • Mutation, Missense / genetics*
  • Pedigree
  • Phenotype
  • Phosvitin / metabolism
  • Sleep Wake Disorders / genetics*
  • Sleep Wake Disorders / physiopathology*
  • Syndrome
  • Time Factors

Substances

  • Caseins
  • Phosvitin
  • Casein Kinase Idelta