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

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.

Genetics of Human Sleep Behavioral Phenotypes

“…Conventionally, to obtain high quantity and quality of DNA, the gold standard is to obtain samples through phlebotomy (Toh et al, 2001;Xu et al, 2005). DNA with optimal quality can be extracted by PAXgene Blood DNA Kit (QIAGEN), GeneCatcher gDNA Blood Kit (Invitrogen), or NucleoSpin Blood (MACHEREY-NAGEL).…”

“…However, it should be noted that certain medical conditions can be comorbid with sleep phenotypes, possibly because the sleep-related variants result in multiple conditions simultaneously. For example, in a FASP kindred, the CSNK1D T44A variant that reduces the activity of casein kinase 1δ was shown to cause both FASP and migraine (Brennan et al, 2013;Xu et al, 2005). Alternatively, sleep-related variants may cosegregate with the variants associated with other medical conditions, thus resulting in comorbidity of sleep phenotypes with these conditions.…”

“…In contrast, it is relatively easy to breed genetically homogeneous mice and to assess sleep phenotypes using the same set of parameters for quantifying human sleep. In this regard, several reports have exemplified the feasibility of utilizing mouse models to study human sleep phenotypes (Hasan et al, 2014;He et al, 2009;Xu et al, 2005Xu et al, , 2007. In addition, since there are only a few affected individuals phenotypically verified in most FASP and FNSS families, it is usually not possible to ascertain statistical significance in these measurements.…”

“…Major breakthroughs in our knowledge of the molecular control of sleep timing and homeostasis have come through studies of familial advanced sleep phase (FASP) and familial natural short sleep (FNSS; He et al, 2009;Jones et al, 1999;Toh et al, 2001;Xu et al, 2005Xu et al, , 2007. FASP and FNSS are Mendelian autosomal dominant sleep phenotypes that significantly deviate from the population norm and run within families.…”

Glucocorticoids and circadian clock control of cell proliferation: At the interface between three dynamic systems

“…Such modifications include phosphorylation of core clock factors, e.g. of PER2, which is phosphorylated on several residues by the kinases CK1, CK1 and CK2, [20][21][22][23] or of CRY1 by AMPK [24]. Other modifications include the ubiquitination of CRYs by F-box type ubiquitin ligases that targets them for M a n u s c r i p t degradation by the proteasome [25][26][27].…”