Neurological disorders

Advanced sleep phase syndrome; Advanced sleep-phase syndrome, familial, 2; Familial advanced sleep phase syndrome 1

Several loss-of-function mutations in the CSNK1D gene have been identified in ASPS patients, including a T44A substitution mutation, and a H46R substitution mutation. The T44A mutation occurs at a highly conserved residue that is found in the casein kinase 1 protein from Drosphila through mammals. Enzymatic anaylsis revealed that the T44A mutant CSNK1D protein displays significantly reduced kinase catalytic activity compared to the wildtype protein. Similarly, the H46R residue also occurs at a highly conserved residue and has been shown to reduce the kinase catalytic activity of the H46R mutant CSNK1D protein by 53% compared to the wildtype protein. Therefore, the ASPS phenotype is associated with a loss-of-function in the catalytic activity of the CSNK1D protein. In animal studies, Drosophila carrying the T44A mutation displayed lengthened circadian cycles. In constrast, mice carrying the same mutation display shortened circadian cycles and a similar phenotype to human ASPS. In addition, overexpression of the CSNK1D gene in the forebrain and striatum of mice results in hyperactivity, decreased anxiety, increased impulsivity, and defective nesting behaviours, potential due to abnormal circadian rythyms. Furthermore, these mice showed paradoxical responses to the injection of dopamine receptor agonists into the brain. In addition, CSNK1D overexpression is associated with decreased expression of the dopamine receptors D1 and D2 in the affected brain regions, indicating a role for the protein in the modulation of dopaminergic signalling in the brain. Advanced sleep phase syndrome (ASPS) is a sleep disorder characterized by the abnormal alteration of the circadian rhythym. Symptoms include falling asleep in the early evening (6:00-8:00 pm) and waking up early in the morning (e.g. 3:00 am). ASPS is a rare disorder that appears to affect men and women equally with a strong genetic association.
 

TranscriptoNET (www.transcriptonet.ca) analysis with mRNA expression data retrieved from the National Center for Biotechnology Information's Gene Expression Omnibus (GEO) database, which was normalized against 60 abundantly and commonly found proteins, indicated altered expression for this protein kinase as shown here as the percent change from normal tissue controls (%CFC) as supported with the Student T-test in the following types of human cancers: Bladder carcinomas (%CFC= +96, p<0.0001); Large B-cell lymphomas (%CFC= +54, p<0.018); Large B-cell lymphomas (%CFC= +54, p<0.023); Malignant pleural mesotheliomas (MPM) tumours (%CFC= +57, p<0.028); and Skin melanomas - malignant (%CFC= +61, p<0.008).

Insertional mutagenesis studies in mice have not yet revealed a role for this protein kinase in mouse cancer oncogenesis.

Percent mutation rates per 100 amino acids length in human cancers: 0.07 % in 24440 diverse cancer specimens. This rate is only -1 % lower and is very similar to the average rate of 0.075 % calculated for human protein kinases in general.

Highest percent mutation rates per 100 amino acids length in human cancers: 0.51 % in 1270 large intestine cancers tested.

Most frequent mutations with the number of reports indicated in brackets: A36V (5), S97P (4).

Only 3 deletions, no insertions or complex mutations.