NPAS3

NPAS3 or Neuronal PAS ___domain protein 3 is a brain-enriched transcription factor belonging to the bHLH-PAS superfamily of transcription factors, the members of which carry out diverse functions, including circadian oscillations, neurogenesis, toxin metabolism, hypoxia, and tracheal development. NPAS3 contains a basic helix-loop-helix structural motif and two PAS ___domain, like the other proteins in the superfamily.

NPAS3
Identifiers
Aliases	NPAS3, neuronal PAS ___domain protein 3, MOP6, PASD6, bHLHe12
External IDs	OMIM: 609430; MGI: 1351610; HomoloGene: 8461; GeneCards: NPAS3; OMA:NPAS3 - orthologs
Gene ___location (Human) Chr. Chromosome 14 (human)[1] Band 14q13.1 Start 32,934,396 bp[1] End 33,820,863 bp[1]
Gene ___location (Mouse) Chr. Chromosome 12 (mouse)[2] Band 12|12 C1 Start 53,248,677 bp[2] End 54,072,175 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in endothelial cell ventricular zone corpus callosum buccal mucosa cell globus pallidus internal globus pallidus external globus pallidus optic nerve inferior ganglion of vagus nerve entorhinal cortex Top expressed in substantia nigra lumbar subsegment of spinal cord deep cerebellar nuclei dorsal tegmental nucleus fossa globus pallidus dorsomedial hypothalamic nucleus ventral tegmental area condyle lateral hypothalamus More reference expression data BioGPS n/a
Gene ontology Molecular function protein dimerization activity DNA binding DNA-binding transcription factor activity, RNA polymerase II-specific protein heterodimerization activity Cellular component nucleoplasm cytosol nucleus Biological process regulation of transcription by RNA polymerase II positive regulation of transcription, DNA-templated transcription, DNA-templated regulation of transcription, DNA-templated developmental process positive regulation of transcription by RNA polymerase II Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 64067 27386 Ensembl ENSG00000151322 ENSMUSG00000021010 UniProt Q8IXF0 Q9QZQ0 RefSeq (mRNA) NM_001164749 NM_001165893 NM_022123 NM_173159 NM_001394988 NM_001394989 NM_013780 RefSeq (protein) NP_001158221 NP_001159365 NP_071406 NP_775182 NP_038808 Location (UCSC) Chr 14: 32.93 – 33.82 Mb Chr 12: 53.25 – 54.07 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

It functions as an heterodimer by binding ARNT2, another memeber of the bHLH-PAS superfamily^[5] .

Function

NPAS3 harbors the largest cluster of human accelerated regions, suggesting it may have played a key role in human evolution ^[6]. Among this accelerated elements, HAR202 is particularly fascinating due to its differential activity between modern humans and archaic species, even though it has only been reported in animal reporter assays^[7].

From the first set of human accelerated regions described in 2006, NPAS3 locus overlaps one of the most accelerated sequences, HAR21 .^[8]

NPAS1 and NPAS3-deficient mice display behavioral abnormalities typical to the animal models of schizophrenia.^[9] Targeting the gene in astrocytes leads to autistic-like behaviours such as reduced vocalization and socialization ^[10].

According to the same study, NPAS1 and NPAS3 disruption leads to reduced expression of reelin, which is also consistently found to be reduced in the brains of human patients with schizophrenia and psychotic bipolar disorder.

Recent advances in mouse models have further characterized NPAS3 function and identified key roles in astrogenesis, adult neurogenesis and in inhibitory interneurons differentiation^[10][11][12].

Clinical significance

Disruption of NPAS3 was found in one family affected by schizophrenia^[13] and NPAS3 gene is thought to be associated with psychiatric illness and learning disability.^[14][15] In a genetic study of several hundred subjects conducted in 2008, interacting haplotypes at the NPAS3 locus were found to affect the risk of schizophrenia and bipolar disorder.^[16]

In a pharmacogenetical study, polymorphisms in NPAS3 gene were highly associated with response to iloperidone, a proposed atypical antipsychotic.^[17]

References

1. GRCh38: Ensembl release 89: ENSG00000151322 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000021010 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Rossi, Joseph J.; Rosenfeld, Jill A.; Chan, Katie M.; Streff, Haley; Nankivell, Victoria; Peet, Daniel J.; Whitelaw, Murray L.; Bersten, David C. (2021-03-23). "Molecular characterisation of rare loss-of-function NPAS3 and NPAS4 variants identified in individuals with neurodevelopmental disorders". Scientific Reports. 11 (1): 6602. doi:10.1038/s41598-021-86041-4. ISSN 2045-2322.
6. Kamm, Gretel B.; Pisciottano, Francisco; Kliger, Rafi; Franchini, Lucía F. (May 2013). "The Developmental Brain Gene NPAS3 Contains the Largest Number of Accelerated Regulatory Sequences in the Human Genome". Molecular Biology and Evolution. 30 (5): 1088–1102. doi:10.1093/molbev/mst023. ISSN 1537-1719. PMC 3670734. PMID 23408798.
7. Caporale, Alfredo Leandro; Cinalli, Alejandro R; Rubinstein, Marcelo; Franchini, Lucía F (2024-10-04). Wittkopp, Patricia (ed.). "The Human Accelerated Region HAR202 Controls NPAS3 Expression in the Developing Forebrain Displaying Differential Enhancer Activity Between Modern and Archaic Human Sequences". Molecular Biology and Evolution. 41 (10). doi:10.1093/molbev/msae186. ISSN 0737-4038. PMC 11461159. PMID 39241178.
8. Pollard KS, Salama SR, Lambert N, Lambot MA, Coppens S, Pedersen JS, Katzman S, King B, Onodera C, Siepel A, Kern AD, Dehay C, Igel H, Ares M, Vanderhaeghen P, Haussler D (Sep 2006). "An RNA gene expressed during cortical development evolved rapidly in humans" (PDF). Nature. 443 (7108): 167–72. Bibcode:2006Natur.443..167P. doi:10.1038/nature05113. PMID 16915236. S2CID 18107797.
9. Erbel-Sieler C, Dudley C, Zhou Y, Wu X, Estill SJ, Han T, Diaz-Arrastia R, Brunskill EW, Potter SS, McKnight SL (Sep 2004). "Behavioral and regulatory abnormalities in mice deficient in the NPAS1 and NPAS3 transcription factors". Proceedings of the National Academy of Sciences of the United States of America. 101 (37): 13648–53. Bibcode:2004PNAS..10113648E. doi:10.1073/pnas.0405310101. PMC 518807. PMID 15347806.
10. Li, Yuanyuan; Fan, Tianda; Li, Xianfeng; Liu, Liqiu; Mao, Fengbiao; Li, Yi; Miao, Zhuang; Zeng, Cheng; Song, Wei; Pan, Jinrong; Zhou, Shutang; Sunday, Mary E.; Wang, Hongbing; Wang, Yan; Sun, Zhong Sheng (2022-08-30). "Npas3 deficiency impairs cortical astrogenesis and induces autistic-like behaviors". Cell Reports. 40 (9). doi:10.1016/j.celrep.2022.111289. ISSN 2211-1247. PMID 36044858.
11. Pieper, Andrew A.; Wu, Xinle; Han, Tina W.; Estill, Sandi Jo; Dang, Quyen; Wu, Leeju C.; Reece-Fincanon, Sarah; Dudley, Carol A.; Richardson, James A.; Brat, Daniel J.; McKnight, Steven L. (2005-09-27). "The neuronal PAS ___domain protein 3 transcription factor controls FGF-mediated adult hippocampal neurogenesis in mice". Proceedings of the National Academy of Sciences. 102 (39): 14052–14057. doi:10.1073/pnas.0506713102. ISSN 0027-8424. PMC 1216832. PMID 16172381.
12. Stanco, Amelia; Pla, Ramón; Vogt, Daniel; Chen, Yiran; Mandal, Shyamali; Walker, Jamie; Hunt, Robert F.; Lindtner, Susan; Erdman, Carolyn A.; Pieper, Andrew A.; Hamilton, Steven P.; Xu, Duan; Baraban, Scott C.; Rubenstein, John L. R. (2014-12-03). "NPAS1 Represses the Generation of Specific Subtypes of Cortical Interneurons". Neuron. 84 (5): 940–953. doi:10.1016/j.neuron.2014.10.040. ISSN 0896-6273. PMID 25467980.
13. Kamnasaran D, Muir WJ, Ferguson-Smith MA, Cox DW (May 2003). "Disruption of the neuronal PAS3 gene in a family affected with schizophrenia". Journal of Medical Genetics. 40 (5): 325–32. doi:10.1136/jmg.40.5.325. PMC 1735455. PMID 12746393.
14. Pickard BS, Malloy MP, Porteous DJ, Blackwood DH, Muir WJ (Jul 2005). "Disruption of a brain transcription factor, NPAS3, is associated with schizophrenia and learning disability". American Journal of Medical Genetics Part B. 136B (1): 26–32. doi:10.1002/ajmg.b.30204. PMID 15924306. S2CID 33879828.
15. Pickard BS, Pieper AA, Porteous DJ, Blackwood DH, Muir WJ (2006). "The NPAS3 gene--emerging evidence for a role in psychiatric illness". Annals of Medicine. 38 (6): 439–48. doi:10.1080/07853890600946500. PMID 17008307.
16. Pickard BS, Christoforou A, Thomson PA, Fawkes A, Evans KL, Morris SW, Porteous DJ, Blackwood DH, Muir WJ (Sep 2009). "Interacting haplotypes at the NPAS3 locus alter risk of schizophrenia and bipolar disorder". Molecular Psychiatry. 14 (9): 874–84. doi:10.1038/mp.2008.24. PMID 18317462.
17. Lavedan C, Volpi S, Mack K, Heaton C, Lannan R, Hamilton J, Licamele L, Wolfgang CD, Polymeropoulos MH (October 2007). "Whole Genome Association Study Identifies Polymorphisms in the NPAS3 Gene Associated With Enhanced Response to Iloperidone Treatment in Patients With Schizophrenia" (PDF). Vanda Pharmaceuticals (Conference poster (American Society of Human Genetics 57th Annual Meeting, San Diego, October 23–27, 2007)). Vanda Pharmaceuticals Inc. Retrieved 27 August 2025.

Further reading

• Kamnasaran D, Muir WJ, Ferguson-Smith MA, Cox DW (May 2003). "Disruption of the neuronal PAS3 gene in a family affected with schizophrenia". Journal of Medical Genetics. 40 (5): 325–32. doi:10.1136/jmg.40.5.325. PMC 1735455. PMID 12746393.
• Moreira F, Kiehl TR, So K, Ajeawung NF, Honculada C, Gould P, Pieper RO, Kamnasaran D (Jul 2011). "NPAS3 demonstrates features of a tumor suppressive role in driving the progression of Astrocytomas". The American Journal of Pathology. 179 (1): 462–76. doi:10.1016/j.ajpath.2011.03.044. PMC 3123785. PMID 21703424.
• Kamnasaran D, Ajewung N, Rana M, Gould P (2010). "393 NPAS3 is a novel late-stage acting progression factor in gliomas with tumour suppressive functions". European Journal of Cancer Supplements. 8 (5): 100. doi:10.1016/S1359-6349(10)71194-0.
• Long PM, Wesley UV, Jaworski DM (2010). "CB-01. Regulation of aminoacylase expression in neuroblastoma". Neuro-Oncology. 12 (Supplement 4): iv7 – iv25. doi:10.1093/neuonc/noq116.s2. PMC 3199169.
• Wong J, Duncan CE, Beveridge NJ, Webster MJ, Cairns MJ, Weickert CS (Mar 2013). "Expression of NPAS3 in the human cortex and evidence of its posttranscriptional regulation by miR-17 during development, with implications for schizophrenia". Schizophrenia Bulletin. 39 (2): 396–406. doi:10.1093/schbul/sbr177. PMC 3576160. PMID 22228753.
• Shin J, Jeong HY, Lee KE, Kim J (Sep 2010). "Isolation and Characterization of Chicken NPAS3". Experimental Neurobiology. 19 (2): 71–4. doi:10.5607/en.2010.19.2.71. PMC 3214776. PMID 22110344.
• Fonseca DJ, Prada CF, Siza LM, Angel D, Gomez YM, Restrepo CM, Douben H, Rivadeneira F, de Klein A, Laissue P (Mar 2012). "A de novo 14q12q13.3 interstitial deletion in a patient affected by a severe neurodevelopmental disorder of unknown origin". American Journal of Medical Genetics Part A. 158A (3): 689–93. doi:10.1002/ajmg.a.35215. PMID 22315208. S2CID 9506804.