ORPHA: 164736; DO: 0110013;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p36.23 | ?Advanced sleep phase syndrome, familial, 3 | 616882 | Autosomal dominant | 3 | PER3 | 603427 |
A number sign (#) is used with this entry because of evidence that familial advanced sleep phase syndrome-3 (FASPS3) is caused by heterozygous mutation in the PER3 gene (603427) on chromosome 1p36. One such family has been reported.
Advanced sleep phase syndrome is characterized by early sleep time (sleep onset) and early morning awakening (sleep offset) (summary by Zhang et al., 2016).
For a discussion of genetic heterogeneity of advanced sleep phase syndrome, see FASPS1 (604348).
Zhang et al. (2016) reported a family in which 3 individuals had advanced sleep phase syndrome, with much earlier sleep onset and offset times compared to unaffected family members and conventional sleepers. In addition, all 3 individuals showed clinical features of seasonal affective disorder (see 608516).
The transmission pattern of FASPS3 in the family reported by Zhang et al. (2016) was consistent with autosomal dominant inheritance.
In 3 affected members of a family with FASPS3 and features of seasonal affective disorder, Zhang et al. (2016) identified heterozygosity for 2 missense mutations in the PER3 gene on the same allele (P415A and H417R; 603427.0001). The mutations, which were found by screening of candidate circadian genes, segregated with the disorder in the family. In vitro luciferase reporter assays showed that the variant allele reduced PER3 repressor activity compared to wildtype. The mutant protein was also expressed at levels lower than control values, due to decreased protein stability, and failed to stabilize the PER1 (602260) and PER2 (603426) proteins, which play critical roles in circadian timing. Expression of the variant allele in transgenic mice resulted in a longer circadian period under constant light and phase shifts of the sleep-wake cycle in a shorter light period, as observed in winter, as well as increased depression-like behavior. Circadian rhythm changes were also observed in Drosophila that expressed the variant allele. The findings suggested that PER3 plays a role in sleep and mood regulation, especially in response to seasonal changes in day length.
Zhang et al. (2016) found that Per3-null mice showed depressive-like behavior which was exacerbated when the photoperiod was shortened, reminiscent of seasonal affective disorder in humans.
Zhang, L., Hirano, A., Hsu, P.-K., Jones, C. R., Sakai, N., Okuro, M., McMahon, T., Yamazaki, M., Xu, Y., Saigoh, N., Saigoh, K., Lin, S.-T., Kaasik, K., Nishino, S., Ptacek, L. J., Fu, Y.-H. A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait. Proc. Nat. Acad. Sci. 113: E1536, 2016. Note: Electronic Article. [PubMed: 26903630] [Full Text: https://doi.org/10.1073/pnas.1600039113]