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. It functions as an heterodimer by binding ARNT2, another member of the bHLH-PAS superfamily.
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| NPAS3 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | NPAS3, neuronal PAS domain protein 3, MOP6, PASD6, bHLHe12 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 609430; MGI: 1351610; HomoloGene: 8461; GeneCards: NPAS3; OMA:NPAS3 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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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.
It functions as an heterodimer by binding ARNT2, another member of the bHLH-PAS superfamily.[5]
Function
[edit]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
[edit]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
[edit]- ^ a b c GRCh38: Ensembl release 89: ENSG00000151322 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021010 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Rossi JJ, Rosenfeld JA, Chan KM, Streff H, Nankivell V, Peet DJ, et al. (March 2021). "Molecular characterisation of rare loss-of-function NPAS3 and NPAS4 variants identified in individuals with neurodevelopmental disorders". Scientific Reports. 11 (1) 6602. Bibcode:2021NatSR..11.6602R. doi:10.1038/s41598-021-86041-4. PMC 7987981. PMID 33758288.
- ^ Kamm GB, Pisciottano F, Kliger R, Franchini LF (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. PMC 3670734. PMID 23408798.
- ^ Caporale AL, Cinalli AR, Rubinstein M, Franchini LF (October 2024). Wittkopp P (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) msae186. doi:10.1093/molbev/msae186. PMC 11461159. PMID 39241178.
- ^ Pollard KS, Salama SR, Lambert N, Lambot MA, Coppens S, Pedersen JS, et al. (September 2006). "An RNA gene expressed during cortical development evolved rapidly in humans". Nature. 443 (7108): 167–172. Bibcode:2006Natur.443..167P. doi:10.1038/nature05113. hdl:2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/51805. PMID 16915236. S2CID 18107797.
- ^ Erbel-Sieler C, Dudley C, Zhou Y, Wu X, Estill SJ, Han T, et al. (September 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): 13648–13653. Bibcode:2004PNAS..10113648E. doi:10.1073/pnas.0405310101. PMC 518807. PMID 15347806.
- ^ a b Li Y, Fan T, Li X, Liu L, Mao F, Li Y, et al. (August 2022). "Npas3 deficiency impairs cortical astrogenesis and induces autistic-like behaviors". Cell Reports. 40 (9) 111289. doi:10.1016/j.celrep.2022.111289. PMID 36044858.
- ^ Pieper AA, Wu X, Han TW, Estill SJ, Dang Q, Wu LC, et al. (September 2005). "The neuronal PAS domain protein 3 transcription factor controls FGF-mediated adult hippocampal neurogenesis in mice". Proceedings of the National Academy of Sciences of the United States of America. 102 (39): 14052–14057. Bibcode:2005PNAS..10214052P. doi:10.1073/pnas.0506713102. PMC 1216832. PMID 16172381.
- ^ Stanco A, Pla R, Vogt D, Chen Y, Mandal S, Walker J, et al. (December 2014). "NPAS1 represses the generation of specific subtypes of cortical interneurons". Neuron. 84 (5): 940–953. doi:10.1016/j.neuron.2014.10.040. PMC 4258152. PMID 25467980.
- ^ 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): 325–332. doi:10.1136/jmg.40.5.325. PMC 1735455. PMID 12746393.
- ^ Pickard BS, Malloy MP, Porteous DJ, Blackwood DH, Muir WJ (July 2005). "Disruption of a brain transcription factor, NPAS3, is associated with schizophrenia and learning disability". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. 136B (1): 26–32. doi:10.1002/ajmg.b.30204. PMID 15924306. S2CID 33879828.
- ^ 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): 439–448. doi:10.1080/07853890600946500. PMID 17008307.
- ^ Pickard BS, Christoforou A, Thomson PA, Fawkes A, Evans KL, Morris SW, et al. (September 2009). "Interacting haplotypes at the NPAS3 locus alter risk of schizophrenia and bipolar disorder". Molecular Psychiatry. 14 (9): 874–884. doi:10.1038/mp.2008.24. PMID 18317462.
- ^ Lavedan C, Volpi S, Mack K, Heaton C, Lannan R, Hamilton J, et al. (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
[edit]- 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): 325–332. doi:10.1136/jmg.40.5.325. PMC 1735455. PMID 12746393.
- Moreira F, Kiehl TR, So K, Ajeawung NF, Honculada C, Gould P, et al. (July 2011). "NPAS3 demonstrates features of a tumor suppressive role in driving the progression of Astrocytomas". The American Journal of Pathology. 179 (1): 462–476. 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 (March 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 (September 2010). "Isolation and Characterization of Chicken NPAS3". Experimental Neurobiology. 19 (2): 71–74. doi:10.5607/en.2010.19.2.71. PMC 3214776. PMID 22110344.
- Fonseca DJ, Prada CF, Siza LM, Angel D, Gomez YM, Restrepo CM, et al. (March 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): 689–693. doi:10.1002/ajmg.a.35215. PMID 22315208. S2CID 9506804.
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