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Gene Review

NPAS2  -  neuronal PAS domain protein 2

Homo sapiens

Synonyms: BHLHE9, Basic-helix-loop-helix-PAS protein MOP4, Class E basic helix-loop-helix protein 9, MOP4, Member of PAS protein 4, ...
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Disease relevance of NPAS2


Psychiatry related information on NPAS2

  • We found that, under conditions of increased sleep need, i.e., at the end of the active period or after sleep deprivation (SD), NPAS2 allows for sleep to occur at times when mice are normally awake [2].

High impact information on NPAS2

  • NPAS2 as a transcriptional regulator of non-rapid eye movement sleep: Genotype and sex interactions [2].
  • We conclude that NPAS2 plays a role in sleep homeostasis, most likely at the level of the thalamus and cortex, where NPAS2 is abundantly expressed [2].
  • Lack of npas2 affected electroencephalogram activity of thalamocortical origin; during non-rapid eye movement sleep (NREMS), activity in the spindle range (10-15 Hz) was reduced, and within the delta range (1-4 Hz), activity shifted toward faster frequencies [2].
  • RNA blotting assays demonstrated the selective presence of NPAS1 and NPAS2 mRNAs in brain and spinal cord tissues of adult mice [3].
  • Similarly, the human NPAS2 gene was assigned to chromosome 2p11.2-2q13, and the mouse Npas2 gene to chromosome 1 at 21-22 centimorgans [3].

Biological context of NPAS2

  • A significant difference between patients and controls was found for NPAS2 471 Leu/Ser (chi(2)=9.90, Bonferroni corrected P=0.035), indicating a recessive effect of the leucine allele on disease susceptibility (chi(2)=6.61, Bonferroni corrected P=0.050) [4].
  • Examples include the neuronal bHLH-PAS carbon monoxide sensor NPAS2 that is implicated in the mammalian circadian clock, the acetobacterial oxygen sensor AxPDEA1 that directs cellulose production, and the rhizobial oxygen sensor FixL, which governs nitrogen fixation [5].
  • In mammals the PAS transcription factors Clock, NPAS2, and BMAL1 regulate gene expression as a function of the day-night cycle [6].
  • Neuronal PAS domain protein 2 (NPAS2) is a mammalian transcription factor that binds DNA as an obligate dimeric partner of BMAL1 and is implicated in the regulation of circadian rhythm [7].
  • Co-transfection experiments in COS cells demonstrated that chicken BMAL1/CLOCK and human BMAL1/MOP4 heterodimers bound the AANAT E box element and enhanced transcription [8].

Associations of NPAS2 with chemical compounds

  • Both PAS domains of NPAS2 were found to bind heme as a prosthetic group, form a gas-regulated sensor, and exert heme-status control of DNA binding in vitro [6].
  • NPAS2-BMAL1 heterodimers, existing in either the apo (heme-free) or holo (heme-loaded) state, bound DNA avidly under favorably reducing ratios of the reduced and oxidized forms of nicotinamide adenine dinucleotide phosphate [7].

Other interactions of NPAS2

  • This effect was CRY-specific, as other known repressors of CLOCK/BMAL1 and NPAS2/ BMAL1 transcriptional activity were not able to induce similar effects [9].
  • Finally, heme-binding transcriptional factors such as Bach1 and NPAS2 regulate the transcription of several genes involved in the synthesis and degradation of heme-hemeproteins [10].
  • Other evidence derives from the relationship of circadian genes, NPAS2 and Clock, to metabolism [11].

Analytical, diagnostic and therapeutic context of NPAS2

  • In situ hybridization assays using brain tissue of postnatal mice revealed an exclusively neuronal pattern of expression for NPAS1 and NPAS2 mRNAs [3].
  • In this population-based case control study (n = 455 cases; 527 controls), we examined the only identified nonsynonymous polymorphism (Ala394Thr; rs2305160) in the largest circadian gene, neuronal PAS domain protein 2 (NPAS2), in order to examine its impact on NHL risk [1].


  1. Ala394Thr polymorphism in the clock gene NPAS2: A circadian modifier for the risk of non-Hodgkin's lymphoma. Zhu, Y., Leaderer, D., Guss, C., Brown, H.N., Zhang, Y., Boyle, P., Stevens, R.G., Hoffman, A., Qin, Q., Han, X., Zheng, T. Int. J. Cancer (2007) [Pubmed]
  2. NPAS2 as a transcriptional regulator of non-rapid eye movement sleep: Genotype and sex interactions. Franken, P., Dudley, C.A., Estill, S.J., Barakat, M., Thomason, R., O'hara, B.F., McKnight, S.L. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  3. Molecular characterization of two mammalian bHLH-PAS domain proteins selectively expressed in the central nervous system. Zhou, Y.D., Barnard, M., Tian, H., Li, X., Ring, H.Z., Francke, U., Shelton, J., Richardson, J., Russell, D.W., McKnight, S.L. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  4. Circadian clock-related polymorphisms in seasonal affective disorder and their relevance to diurnal preference. Johansson, C., Willeit, M., Smedh, C., Ekholm, J., Paunio, T., Kieseppä, T., Lichtermann, D., Praschak-Rieder, N., Neumeister, A., Nilsson, L.G., Kasper, S., Peltonen, L., Adolfsson, R., Schalling, M., Partonen, T. Neuropsychopharmacology (2003) [Pubmed]
  5. Signal transduction by heme-containing PAS-domain proteins. Gilles-Gonzalez, M.A., Gonzalez, G. J. Appl. Physiol. (2004) [Pubmed]
  6. Light pulse-induced heme and iron-associated transcripts in mouse brain: a microarray analysis. Ben-Shlomo, R., Akhtar, R.A., Collins, B.H., Judah, D.J., Davies, R., Kyriacou, C.P. Chronobiol. Int. (2005) [Pubmed]
  7. NPAS2: a gas-responsive transcription factor. Dioum, E.M., Rutter, J., Tuckerman, J.R., Gonzalez, G., Gilles-Gonzalez, M.A., McKnight, S.L. Science (2002) [Pubmed]
  8. Characterization of the chicken serotonin N-acetyltransferase gene. Activation via clock gene heterodimer/E box interaction. Chong, N.W., Bernard, M., Klein, D.C. J. Biol. Chem. (2000) [Pubmed]
  9. Post-translational regulation of circadian transcriptional CLOCK(NPAS2)/BMAL1 complex by CRYPTOCHROMES. Kondratov, R.V., Kondratova, A.A., Lee, C., Gorbacheva, V.Y., Chernov, M.V., Antoch, M.P. Cell Cycle (2006) [Pubmed]
  10. Aquisition, mobilization and utilization of cellular iron and heme: endless findings and growing evidence of tight regulation. Taketani, S. Tohoku J. Exp. Med. (2005) [Pubmed]
  11. Sleep: a functional enigma. Greene, R., Siegel, J. Neuromolecular Med. (2004) [Pubmed]
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