Biology: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.[1]
Function
NPAS3 harbors the largest cluster of human accelerated regions, suggesting it may have played a key role in human evolution.[2] 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.[3]
From the first set of human accelerated regions described in 2006, NPAS3 locus overlaps one of the most accelerated sequences, HAR21 .[4]
NPAS1 and NPAS3-deficient mice display behavioral abnormalities typical to the animal models of schizophrenia.[5] Targeting the gene in astrocytes leads to autistic-like behaviours such as reduced vocalization and socialization.[6]
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.[6][7][8]
Clinical significance
Disruption of NPAS3 was found in one family affected by schizophrenia[9] and NPAS3 gene is thought to be associated with psychiatric illness and learning disability.[10][11] 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.[12]
In a pharmacogenetical study, polymorphisms in NPAS3 gene were highly associated with response to iloperidone, a proposed atypical antipsychotic.[13]
References
- ↑ "Molecular characterisation of rare loss-of-function NPAS3 and NPAS4 variants identified in individuals with neurodevelopmental disorders". Scientific Reports 11 (1). March 2021. doi:10.1038/s41598-021-86041-4. PMID 33758288. Bibcode: 2021NatSR..11.6602R.
- ↑ "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. May 2013. doi:10.1093/molbev/mst023. PMID 23408798.
- ↑ "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). October 2024. doi:10.1093/molbev/msae186. PMID 39241178.
- ↑ "An RNA gene expressed during cortical development evolved rapidly in humans". Nature 443 (7108): 167–172. September 2006. doi:10.1038/nature05113. PMID 16915236. Bibcode: 2006Natur.443..167P.
- ↑ "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. September 2004. doi:10.1073/pnas.0405310101. PMID 15347806. Bibcode: 2004PNAS..10113648E.
- ↑ 6.0 6.1 "Npas3 deficiency impairs cortical astrogenesis and induces autistic-like behaviors" (in English). Cell Reports 40 (9). August 2022. doi:10.1016/j.celrep.2022.111289. PMID 36044858.
- ↑ "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. September 2005. doi:10.1073/pnas.0506713102. PMID 16172381. Bibcode: 2005PNAS..10214052P.
- ↑ "NPAS1 represses the generation of specific subtypes of cortical interneurons" (in English). Neuron 84 (5): 940–953. December 2014. doi:10.1016/j.neuron.2014.10.040. PMID 25467980.
- ↑ "Disruption of the neuronal PAS3 gene in a family affected with schizophrenia". Journal of Medical Genetics 40 (5): 325–332. May 2003. doi:10.1136/jmg.40.5.325. PMID 12746393.
- ↑ "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. July 2005. doi:10.1002/ajmg.b.30204. PMID 15924306.
- ↑ "The NPAS3 gene--emerging evidence for a role in psychiatric illness". Annals of Medicine 38 (6): 439–448. 2006. doi:10.1080/07853890600946500. PMID 17008307.
- ↑ "Interacting haplotypes at the NPAS3 locus alter risk of schizophrenia and bipolar disorder". Molecular Psychiatry 14 (9): 874–884. September 2009. doi:10.1038/mp.2008.24. PMID 18317462.
- ↑ "Whole Genome Association Study Identifies Polymorphisms in the NPAS3 Gene Associated With Enhanced Response to Iloperidone Treatment in Patients With Schizophrenia" (in English). Vanda Pharmaceuticals Inc.. October 2007. https://media.corporate-ir.net/media_files/irol/19/196233/VNU-07-0710-04_NPAS_FINAL.pdf.
Further reading
- "Disruption of the neuronal PAS3 gene in a family affected with schizophrenia". Journal of Medical Genetics 40 (5): 325–332. May 2003. doi:10.1136/jmg.40.5.325. PMID 12746393.
- "NPAS3 demonstrates features of a tumor suppressive role in driving the progression of Astrocytomas". The American Journal of Pathology 179 (1): 462–476. July 2011. doi:10.1016/j.ajpath.2011.03.044. PMID 21703424.
- "393 NPAS3 is a novel late-stage acting progression factor in gliomas with tumour suppressive functions". European Journal of Cancer Supplements 8 (5): 100. 2010. doi:10.1016/S1359-6349(10)71194-0.
- "CB-01. Regulation of aminoacylase expression in neuroblastoma". Neuro-Oncology 12 (Supplement 4): iv7–iv25. 2010. doi:10.1093/neuonc/noq116.s2.
- "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. March 2013. doi:10.1093/schbul/sbr177. PMID 22228753.
- "Isolation and Characterization of Chicken NPAS3". Experimental Neurobiology 19 (2): 71–74. September 2010. doi:10.5607/en.2010.19.2.71. PMID 22110344.
- "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. March 2012. doi:10.1002/ajmg.a.35215. PMID 22315208.
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