{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNPAS3 is a neuronal basic helix‐loop‐helix Per–Arnt–Sim (bHLH-PAS) transcription factor that has emerged as a critical player in neuropsychiatric disorders. Genetic studies have revealed that chromosomal translocations and haploinsufficiency affecting NPAS3 are associated with schizophrenia and bipolar disorder; moreover, single nucleotide polymorphisms in NPAS3 have been linked to differences in antipsychotic treatment response. These findings underscore the gene’s importance in shaping psychiatric risk and treatment outcomes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDuring brain development, NPAS3 is robustly expressed in regions critical for neurogenesis such as the hippocampal subgranular zone and the maturing neocortex. Its activity influences neuronal differentiation, cell cycle regulation, and the maintenance of adult neurogenesis. Furthermore, posttranscriptional mechanisms—including regulation by microRNAs—modulate NPAS3 protein levels during normal cortical development. Disruption of NPAS3 in animal models has been associated with impaired neurogenesis and behavioral deficits, highlighting its essential role in neural development and function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nComparative genomic analyses have shown that NPAS3 contains one of the densest clusters of human-accelerated noncoding elements, suggesting that evolutionary modifications in its regulatory regions may have contributed to human-specific cognitive traits and brain complexity. Functional assays in transgenic models demonstrate that these human-accelerated elements can drive distinct spatiotemporal expression patterns, thereby potentially influencing the developmental trajectory of the human nervous system. Notably, however, sequence variations in these regions may not uniformly translate into increased disease risk."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, NPAS3 functions by heterodimerizing with aryl hydrocarbon receptor nuclear translocator (ARNT) proteins—a process elucidated by crystal structure studies that reveal multiple ligand-binding pockets within the NPAS3-ARNT complexes, hinting at possible regulation by small molecules. NPAS3 influences a diverse array of downstream transcriptional targets, including genes implicated in neurogenesis and metabolic regulation, and rare loss-of-function variants in NPAS3 further support its fundamental role in maintaining proper brain function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its developmental roles, NPAS3 has been implicated in the regulation of glial differentiation, notably influencing astrogenesis, and has been shown to act as a tumor suppressor in malignant astrocytomas, with loss of NPAS3 correlating with poorer clinical outcomes. Moreover, aberrant aggregation of NPAS3 protein has been detected in the serum of patients with schizophrenia, suggesting that NPAS3 dysfunction may also manifest at the protein homeostasis level, potentially serving as a biomarker for psychiatric pathology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "D Kamnasaran, W J Muir, M A Ferguson-Smith, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Disruption of the neuronal PAS3 gene in a family affected with schizophrenia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Med Genet (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/jmg.40.5.325"}], "href": "https://doi.org/10.1136/jmg.40.5.325"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12746393"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12746393"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "B S Pickard, A Christoforou, P A Thomson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Interacting haplotypes at the NPAS3 locus alter risk of schizophrenia and bipolar disorder."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Psychiatry (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/mp.2008.24"}], "href": "https://doi.org/10.1038/mp.2008.24"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18317462"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18317462"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "C Lavedan, L Licamele, S Volpi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association of the NPAS3 gene and five other loci with response to the antipsychotic iloperidone identified in a whole genome association study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Psychiatry (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/mp.2008.56"}], "href": "https://doi.org/10.1038/mp.2008.56"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18521090"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18521090"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Simona Volpi, Steven G Potkin, Anil K Malhotra, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Applicability of a genetic signature for enhanced iloperidone efficacy in the treatment of schizophrenia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Psychiatry (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4088/jcp.08m04391"}], "href": "https://doi.org/10.4088/jcp.08m04391"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19573479"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19573479"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Georgina Macintyre, Tyler Alford, Lan Xiong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association of NPAS3 exonic variation with schizophrenia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Schizophr Res (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.schres.2010.04.002"}], "href": "https://doi.org/10.1016/j.schres.2010.04.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20466522"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20466522"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "P Gould, D Kamnasaran "}, {"type": "b", "children": [{"type": "t", "text": "Immunohistochemical analyses of NPAS3 expression in the developing human fetal brain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Anat Histol Embryol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1439-0264.2010.01059.x"}], "href": "https://doi.org/10.1111/j.1439-0264.2010.01059.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21306425"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21306425"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Jenny Wong, Carlotta E Duncan, Natalie J Beveridge, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression of NPAS3 in the human cortex and evidence of its posttranscriptional regulation by miR-17 during development, with implications for schizophrenia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Schizophr Bull (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/schbul/sbr177"}], "href": "https://doi.org/10.1093/schbul/sbr177"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22228753"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22228753"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Jacob J Michaelson, Min-Kyoo Shin, Jin-Young Koh, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Neuronal PAS Domain Proteins 1 and 3 Are Master Regulators of Neuropsychiatric Risk Genes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biol Psychiatry (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.biopsych.2017.03.021"}], "href": "https://doi.org/10.1016/j.biopsych.2017.03.021"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28499489"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28499489"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Leiah M Luoma, Fred B Berry "}, {"type": "b", "children": [{"type": "t", "text": "Molecular analysis of NPAS3 functional domains and variants."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Mol Biol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12867-018-0117-4"}], "href": "https://doi.org/10.1186/s12867-018-0117-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30509165"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30509165"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Gretel B Kamm, Francisco Pisciottano, Rafi Kliger, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The developmental brain gene NPAS3 contains the largest number of accelerated regulatory sequences in the human genome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Evol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/molbev/mst023"}], "href": "https://doi.org/10.1093/molbev/mst023"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23408798"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23408798"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Gretel B Kamm, Rodrigo López-Leal, Juan R Lorenzo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A fast-evolving human NPAS3 enhancer gained reporter expression in the developing forebrain of transgenic mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Philos Trans R Soc Lond B Biol Sci (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1098/rstb.2013.0019"}], "href": "https://doi.org/10.1098/rstb.2013.0019"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24218632"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24218632"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Javier González-Peñas, Manuel Arrojo, Eduardo Paz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cumulative role of rare and common putative functional genetic variants at NPAS3 in schizophrenia susceptibility."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet B Neuropsychiatr Genet (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.b.32324"}], "href": "https://doi.org/10.1002/ajmg.b.32324"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25982957"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25982957"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Dalei Wu, Xiaoyu Su, Nalini Potluri, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NPAS1-ARNT and NPAS3-ARNT crystal structures implicate the bHLH-PAS family as multi-ligand binding transcription factors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.18790"}], "href": "https://doi.org/10.7554/eLife.18790"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27782878"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27782878"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "L Sha, L MacIntyre, J A Machell, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transcriptional regulation of neurodevelopmental and metabolic pathways by NPAS3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Psychiatry (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/mp.2011.73"}], "href": "https://doi.org/10.1038/mp.2011.73"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21709683"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21709683"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Joseph J Rossi, Jill A Rosenfeld, Katie M Chan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Molecular characterisation of rare loss-of-function NPAS3 and NPAS4 variants identified in individuals with neurodevelopmental disorders."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-021-86041-4"}], "href": "https://doi.org/10.1038/s41598-021-86041-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33758288"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33758288"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Yuanyuan Li, Tianda Fan, Xianfeng Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Npas3 deficiency impairs cortical astrogenesis and induces autistic-like behaviors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2022.111289"}], "href": "https://doi.org/10.1016/j.celrep.2022.111289"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36044858"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36044858"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Frederico Moreira, Tim-Rasmus Kiehl, Kelvin So, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NPAS3 demonstrates features of a tumor suppressive role in driving the progression of Astrocytomas."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Pathol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajpath.2011.03.044"}], "href": "https://doi.org/10.1016/j.ajpath.2011.03.044"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21703424"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21703424"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Aristea Pavešić Radonja, Sandra Blažević Zelić, Gordana Rubeša, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SYMPTOM SEVERITY IN SCHIZOPHRENIA PATIENTS WITH NPAS3, DYSBINDIN-1 AND/OR TRIOBP PROTEIN PATHOLOGY IN THEIR BLOOD SERUM: A PANSS-BASED FOLLOW UP STUDY."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Psychiatr Danub (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.24869/psyd.2023.180"}], "href": "https://doi.org/10.24869/psyd.2023.180"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37480305"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37480305"}]}]}]}