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Gene Review

PER2  -  period circadian clock 2

Homo sapiens

Synonyms: Circadian clock protein PERIOD 2, FASPS, FASPS1, KIAA0347, Period circadian protein homolog 2, ...
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Disease relevance of PER2


Psychiatry related information on PER2


High impact information on PER2

  • We show that phosphorylation at S662 leads to increased PER2 transcription and suggest that phosphorylation at another site leads to PER2 degradation [8].
  • Altering CKIdelta dosage modulates the S662 phenotype demonstrating that CKIdelta can regulate period through PER2 in vivo [8].
  • A mutation in human Period 2 (hPER2), a gene crucial for resetting the central clock in response to light, is associated with familial advanced sleep phase syndrome (FASPS), an autosomal dominant condition with early morning awakening and early sleep times [8].
  • Thus, a variant in human sleep behavior can be attributed to a missense mutation in a clock component, hPER2, which alters the circadian period [9].
  • Both PER1 and PER2 proteins share several regions of homology with the Drosophila PER protein, including the protein dimerization PAS domain [10].

Chemical compound and disease context of PER2

  • OBJECTIVE: To review the safety and efficacy of the very-low-dose combination of perindopril 2 mg and indapamide 0.625 mg (Per2/Ind0.625) in essential hypertension, in relation to blood pressure control and target-organ damage [11].

Biological context of PER2


Anatomical context of PER2


Associations of PER2 with chemical compounds

  • Interestingly, despite normal melatonin and cortisol secretion patterns, two groups of subjects could be distinguished with significantly different mean PER2 and BMAL1 acrophases [21].
  • We have investigated three other single-nucleotide polymorphisms in the hPER2 gene, one downstream of the transcription start site (C-1228T), one in exon 2 in the 5'-untranslated region (5'-UTR) (C111G), and one missense mutation (G3853A) causing a glycine to glutamine substitution in the predicted protein [14].
  • The blunting of the PER2 rhythm at these phases of the cycle is abolished by ovariectomy and restored by phasic estrogen replacement suggesting that fluctuations in estrogen levels or their sequelae are necessary to produce these effects [22].
  • Daily limited access to sucrose or saccharine in freely fed rats or scheduled access to saline in sodium-deprived rats had no effect on these PER2 rhythms [23].
  • As with light, muscimol alters circadian phase, and daytime phase alterations induced by muscimol are associated with significant decreases in Per2 mRNA [24].

Regulatory relationships of PER2

  • The NMDA receptor antagonist AP5 and the AMPA/kainate receptor antagonist DNQX inhibited the ability of light and NMDA to acutely increase Per2 mRNA levels in the SCN [25].
  • Per2 has antisense Alu elements in its 3'UTR region, making it susceptible to the regulation of other protein-coding RNAs with sense Alu elements, and Pol-III transcribed Alus [26].

Other interactions of PER2

  • This article discusses approaches, limitations, and applicable protocols to study the regulation of cellular localization of mammalian clock proteins, with a particular focus on mammalian CRY1 and PER2 proteins [27].
  • BMAL1 oscillated with approximately the same phase as PER2, instead of being anti-phasic as anticipated from data previously obtained in other peripheral tissues [21].
  • CKIepsilon (casein kinase Iepsilon) has been postulated to prime PER2 for degradation [28].
  • For instance, a point mutation in a human clock gene (Per2) was shown to produce the rare advanced sleep phase syndrome, whereas a functional polymorphism in Per3 is associated with the more frequent delayed sleep phase syndrome [29].
  • These results suggest that the activation of NMDA receptor is a critical step for photic induction of Per1 and Per2 transcripts in the SCN, which are linked to a photic behavioral entrainment [30].

Analytical, diagnostic and therapeutic context of PER2


  1. Differential effects of PER2 phosphorylation: molecular basis for the human familial advanced sleep phase syndrome (FASPS). Vanselow, K., Vanselow, J.T., Westermark, P.O., Reischl, S., Maier, B., Korte, T., Herrmann, A., Herzel, H., Schlosser, A., Kramer, A. Genes Dev. (2006) [Pubmed]
  2. Deregulated expression of the PER1, PER2 and PER3 genes in breast cancers. Chen, S.T., Choo, K.B., Hou, M.F., Yeh, K.T., Kuo, S.J., Chang, J.G. Carcinogenesis (2005) [Pubmed]
  3. An outbreak of extended-spectrum, beta-lactamase-producing Salmonella senftenberg in a burns ward. Revathi, G., Shannon, K.P., Stapleton, P.D., Jain, B.K., French, G.L. J. Hosp. Infect. (1998) [Pubmed]
  4. Transcription profiling of C/EBP targets identifies Per2 as a gene implicated in myeloid leukemia. Gery, S., Gombart, A.F., Yi, W.S., Koeffler, C., Hofmann, W.K., Koeffler, H.P. Blood (2005) [Pubmed]
  5. Extended-spectrum beta-lactamases in enterobacteriaceae in Buenos Aires, Argentina, public hospitals. Quinteros, M., Radice, M., Gardella, N., Rodriguez, M.M., Costa, N., Korbenfeld, D., Couto, E., Gutkind, G. Antimicrob. Agents Chemother. (2003) [Pubmed]
  6. The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption. Spanagel, R., Pendyala, G., Abarca, C., Zghoul, T., Sanchis-Segura, C., Magnone, M.C., Lascorz, J., Depner, M., Holzberg, D., Soyka, M., Schreiber, S., Matsuda, F., Lathrop, M., Schumann, G., Albrecht, U. Nat. Med. (2005) [Pubmed]
  7. Case study: differences in human Per2 gene expression, body temperature, cortisol, and melatonin parameters in remission and hypersomnia in a patient with recurrent hypersomnia. Tomoda, A., Joudoi, T., Kawatani, J., Ohmura, T., Hamada, A., Tonooka, S., Miike, T. Chronobiol. Int. (2003) [Pubmed]
  8. Modeling of a Human Circadian Mutation Yields Insights into Clock Regulation by PER2. Xu, Y., Toh, K.L., Jones, C.R., Shin, J.Y., Fu, Y.H., Pt??cek, L.J. Cell (2007) [Pubmed]
  9. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Toh, K.L., Jones, C.R., He, Y., Eide, E.J., Hinz, W.A., Virshup, D.M., Ptácek, L.J., Fu, Y.H. Science (2001) [Pubmed]
  10. Two period homologs: circadian expression and photic regulation in the suprachiasmatic nuclei. Shearman, L.P., Zylka, M.J., Weaver, D.R., Kolakowski, L.F., Reppert, S.M. Neuron (1997) [Pubmed]
  11. Very-low-dose combination of perindopril and indapamide: efficacy on blood pressure and target-organ damage. Laurent, S. Journal of hypertension. Supplement : official journal of the International Society of Hypertension. (2003) [Pubmed]
  12. Nuclear entry mechanism of rat PER2 (rPER2): role of rPER2 in nuclear localization of CRY protein. Miyazaki, K., Mesaki, M., Ishida, N. Mol. Cell. Biol. (2001) [Pubmed]
  13. Evening exposure to blue light stimulates the expression of the clock gene PER2 in humans. Cajochen, C., Jud, C., Münch, M., Kobialka, S., Wirz-Justice, A., Albrecht, U. Eur. J. Neurosci. (2006) [Pubmed]
  14. A single-nucleotide polymorphism in the 5'-untranslated region of the hPER2 gene is associated with diurnal preference. Carpen, J.D., Archer, S.N., Skene, D.J., Smits, M., von Schantz, M. Journal of sleep research. (2005) [Pubmed]
  15. Molecular oscillation of per1 and per2 genes in the rodent brain: an in situ hybridization and molecular biological study. Matsui, D., Takekida, S., Okamura, H. The Kobe journal of medical sciences. (2005) [Pubmed]
  16. Temporal and spatial distribution of immunoreactive PER1 and PER2 proteins in the suprachiasmatic nucleus and peri-suprachiasmatic region of the diurnal grass rat (Arvicanthis niloticus). Ramanathan, C., Nunez, A.A., Martinez, G.S., Schwartz, M.D., Smale, L. Brain Res. (2006) [Pubmed]
  17. Pinealectomy does not affect diurnal PER2 expression in the rat limbic forebrain. Amir, S., Harbour, V.L., Robinson, B. Neurosci. Lett. (2006) [Pubmed]
  18. Up-regulation of per mRNA expression by parathyroid hormone through a protein kinase A-CREB-dependent mechanism in chondrocytes. Hinoi, E., Ueshima, T., Hojo, H., Iemata, M., Takarada, T., Yoneda, Y. J. Biol. Chem. (2006) [Pubmed]
  19. Evidence supporting a circadian control of natural killer cell function. Arjona, A., Sarkar, D.K. Brain Behav. Immun. (2006) [Pubmed]
  20. Evidence of an oscillating peripheral clock in an equine fibroblast cell line and adipose tissue but not in peripheral blood. Murphy, B.A., Vick, M.M., Sessions, D.R., Cook, R.F., Fitzgerald, B.P. Journal of comparative physiology. A, Neuroethology, sensory, neural, and behavioral physiology. (2006) [Pubmed]
  21. Atypical patterns of circadian clock gene expression in human peripheral blood mononuclear cells. Teboul, M., Barrat-Petit, M.A., Li, X.M., Claustrat, B., Formento, J.L., Delaunay, F., Lévi, F., Milano, G. J. Mol. Med. (2005) [Pubmed]
  22. The expression of the clock protein PER2 in the limbic forebrain is modulated by the estrous cycle. Perrin, J.S., Segall, L.A., Harbour, V.L., Woodside, B., Amir, S. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  23. Restricted access to food, but not sucrose, saccharine, or salt, synchronizes the expression of Period2 protein in the limbic forebrain. Waddington Lamont, E., Harbour, V.L., Barry-Shaw, J., Renteria Diaz, L., Robinson, B., Stewart, J., Amir, S. Neuroscience (2007) [Pubmed]
  24. Light and GABA receptor activation alter Period mRNA levels in the SCN of diurnal Nile grass rats. Novak, C.M., Ehlen, J.C., Paul, K.N., Fukuhara, C., Albers, H.E. Eur. J. Neurosci. (2006) [Pubmed]
  25. AMPA/kainate receptor antagonist DNQX blocks the acute increase of Per2 mRNA levels in most but not all areas of the SCN. Paul, K.N., Fukuhara, C., Karom, M., Tosini, G., Albers, H.E. Brain Res. Mol. Brain Res. (2005) [Pubmed]
  26. A gene expression restriction network mediated by sense and antisense Alu sequences located on protein-coding messenger RNAs. Liang, K.H., Yeh, C.T. BMC. Genomics. (2013) [Pubmed]
  27. Nucleocytoplasmic shuttling of clock proteins. Tamanini, F., Yagita, K., Okamura, H., van der Horst, G.T. Meth. Enzymol. (2005) [Pubmed]
  28. Control of mammalian circadian rhythm by CKIepsilon-regulated proteasome-mediated PER2 degradation. Eide, E.J., Woolf, M.F., Kang, H., Woolf, P., Hurst, W., Camacho, F., Vielhaber, E.L., Giovanni, A., Virshup, D.M. Mol. Cell. Biol. (2005) [Pubmed]
  29. Genetics of the sleep-wake cycle and its disorders. Hamet, P., Tremblay, J. Metab. Clin. Exp. (2006) [Pubmed]
  30. Correlative association between N-methyl-D-aspartate receptor-mediated expression of period genes in the suprachiasmatic nucleus and phase shifts in behavior with photic entrainment of clock in hamsters. Moriya, T., Horikawa, K., Akiyama, M., Shibata, S. Mol. Pharmacol. (2000) [Pubmed]
  31. Photoperiodic regulation of PER1 and PER2 protein expression in rat peripheral tissues. Bendov??, Z., Sumov??, S. Physiological research / Academia Scientiarum Bohemoslovaca (2006) [Pubmed]
  32. Thyroidectomy alters the daily pattern of expression of the clock protein, PER2, in the oval nucleus of the bed nucleus of the stria terminalis and central nucleus of the amygdala in rats. Amir, S., Robinson, B. Neurosci. Lett. (2006) [Pubmed]
  33. Protein phosphatase 1 regulates the stability of the circadian protein PER2. Gallego, M., Kang, H., Virshup, D.M. Biochem. J. (2006) [Pubmed]
  34. Neuropeptide Y rapidly reduces Period 1 and Period 2 mRNA levels in the hamster suprachiasmatic nucleus. Fukuhara, C., Brewer, J.M., Dirden, J.C., Bittman, E.L., Tosini, G., Harrington, M.E. Neurosci. Lett. (2001) [Pubmed]
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