Functional consequences of a CKIδ mutation causing familial advanced sleep phase syndrome

  title={Functional consequences of a CKI$\delta$ mutation causing familial advanced sleep phase syndrome},
  author={Ying Xu and Quasar Saleem Padiath and Robert E. Shapiro and Christopher R. Jones and Susan C. Wu and Noriko Saigoh and Kazumasa Saigoh and Louis J. Pt{\'a}{\vc}ek and Ying-Hui Fu},
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… 
A Cryptochrome 2 mutation yields advanced sleep phase in humans
It is demonstrated that CRY2 stability controlled by FBXL3 plays a key role in the regulation of human sleep wake behavior.
Casein Kinase 1-dependent Phosphorylation of Familial Advanced Sleep Phase Syndrome-associated Residues Controls PERIOD 2 Stability*
Phospho-specific antibodies are used to show that PER2 is phosphorylated on Ser-662 and flanking casein kinase (CK) sites in vivo and imply that the FASPS phosphorylation cluster antagonizes PER2 degradation.
Differential effects of PER2 phosphorylation: molecular basis for the human familial advanced sleep phase syndrome (FASPS).
Interference with specific aspects of mPER2 phosphorylation leads to either short or long periods in oscillating fibroblasts, which explains not only the FASPS phenotype, but also the effect of the tau mutation in hamster as well as the doubletime mutants (dbtS and dbtL ) in Drosophila.
Circadian rhythms in the CNS and peripheral clock disorders: human sleep disorders and clock genes.
  • T. Ebisawa
  • Biology
    Journal of pharmacological sciences
  • 2007
Findings suggest that further gene variations are involved in human circadian activity, and many of the CRSD-relevant variations reported to date seem to affect the phosphorylation status of the clock proteins.
A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait
The identified rare variants in the PERIOD3 gene in persons with both altered sleep behavior and features of seasonal affective disorder recapitulate circadian and mood phenotypes in mouse models, suggesting that PER3 may be a nexus for sleep and mood regulation while fine-tuning these processes to adapt to seasonal changes.
The Genetic Regulation of Human Sleep-Wake Rhythms and Patterns
A novel quantitative trait locus on mouse chromosome 18, "era1," modifies the entrainment of circadian rhythms.
Genetic variability in the circadian response to light may, in part, explain the variance in phase angle of entrainment in this segregating mouse population.
A missense variant in PER2 is associated with delayed sleep–wake phase disorder in a Japanese population
Low-frequency nonsense and missense variants in circadian rhythm-related genes were extracted by integration of genetic variation databases and in silico assessment and narrowed down the candidates to six variants to examine whether the six variants are associated with DSWPD.


An hPer2 Phosphorylation Site Mutation in Familial Advanced Sleep Phase Syndrome
A variant in human sleep behavior can be attributed to a missense mutation in a clock component, hPER2, which alters the circadian period.
Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau.
The tau mutation is a semidominant autosomal allele that dramatically shortens period length of circadian rhythms in Syrian hamsters and the mechanism by which the mutation leads to the observed aberrant circadian phenotype in mutant animals is proposed.
A role for CK2 in the Drosophila circadian oscillator
It is shown that CK2β is localized within clock neurons and that the clock proteins Period and Timeless accumulate to abnormally high levels in the Andante mutant, suggesting a function for CK2-dependent phosphorylation in the molecular oscillator.
Direct Association between Mouse PERIOD and CKIε Is Critical for a Functioning Circadian Clock
It is proposed that the CKIε-binding domain is critical not only for mPER phosphorylation but also for a functioning circadian clock.
Drosophila doubletime Mutations Which either Shorten or Lengthen the Period of Circadian Rhythms Decrease the Protein Kinase Activity of Casein Kinase I
Low enzyme activity is associated with both short-period and long-period phenotypes of DBT in Drosophila melanogaster.
A mutation of the circadian system in golden hamsters.
A mutation has been found that dramatically shortens the period of the circadian locomotor rhythm of golden hamsters, and animals that carry the mutant alleles exhibit abnormal entrainment to 24-hour light:dark cycles or are unable to entrain.
A role for casein kinase 2α in the Drosophila circadian clock
It is shown that the catalytic subunit of Drosophila casein kinase 2 (CK2α) is expressed predominantly in the cytoplasm of key circadian pacemaker neurons, and proposed that CK2 is an evolutionary link between the divergent circadian systems of animals, plants and fungi.
Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior.
The power of ENU mutagenesis combined with the ability to clone murine genes by map position provides a generally applicable approach to study complex behavior in mammals.