NPAS3 explained

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 basic helix-loop-helix structural motif and PAS domain, like the other proteins in the superfamily.

Function

NPAS3 is also known as human accelerated region 21. It may, therefore, have played a key role in differentiating humans from apes.^[1]

NPAS1 and NPAS3-deficient mice display behavioral abnormalities typical to the animal models of schizophrenia.^[2]

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. Among the 49 genomic regions that undergone rapid changes in humans compared with their evolutionary ancestors, NPAS3 was found to be located in the region 21.^[1]

Clinical significance

Disruption of NPAS3 was found in one family affected by schizophrenia^[3] and NPAS3 gene is thought to be associated with psychiatric illness and learning disability.^{[4] [5]} 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.^[6]

In a pharmacogenetical study, polymorphisms in NPAS3 gene were highly associated with response to iloperidone, a proposed atypical antipsychotic.^[7]

Further reading

• Kamnasaran D, Muir WJ, Ferguson-Smith MA, Cox DW . Disruption of the neuronal PAS3 gene in a family affected with schizophrenia . Journal of Medical Genetics . 40 . 5 . 325–32 . May 2003 . 12746393 . 1735455 . 10.1136/jmg.40.5.325 .
• Moreira F, Kiehl TR, So K, Ajeawung NF, Honculada C, Gould P, Pieper RO, Kamnasaran D . NPAS3 demonstrates features of a tumor suppressive role in driving the progression of Astrocytomas . The American Journal of Pathology . 179 . 1 . 462–76 . Jul 2011 . 21703424 . 3123785 . 10.1016/j.ajpath.2011.03.044 .
• Kamnasaran D, Ajewung N, Rana M, Gould P . 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 . 10.1016/S1359-6349(10)71194-0 .
• Long PM, Wesley UV, Jaworski DM . CB-01. Regulation of aminoacylase expression in neuroblastoma . Neuro-Oncology . 12 . Supplement 4 . iv7–iv25 . 2010 . 10.1093/neuonc/noq116.s2 . 3199169 .
• Wong J, Duncan CE, Beveridge NJ, Webster MJ, Cairns MJ, Weickert CS . 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 . Mar 2013 . 22228753 . 10.1093/schbul/sbr177 . 3576160 .
• Shin J, Jeong HY, Lee KE, Kim J . Isolation and Characterization of Chicken NPAS3 . Experimental Neurobiology . 19 . 2 . 71–4 . Sep 2010 . 22110344 . 3214776 . 10.5607/en.2010.19.2.71 .
• Fonseca DJ, Prada CF, Siza LM, Angel D, Gomez YM, Restrepo CM, Douben H, Rivadeneira F, de Klein A, Laissue P . 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 . Mar 2012 . 22315208 . 10.1002/ajmg.a.35215 . 9506804 .

Notes and References

1. 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 . An RNA gene expressed during cortical development evolved rapidly in humans . Nature . 443 . 7108 . 167–72 . Sep 2006 . 16915236 . 10.1038/nature05113 . 2006Natur.443..167P . 18107797 .
2. Erbel-Sieler C, Dudley C, Zhou Y, Wu X, Estill SJ, Han T, Diaz-Arrastia R, Brunskill EW, Potter SS, McKnight SL . 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 . Sep 2004 . 15347806 . 518807 . 10.1073/pnas.0405310101 . 2004PNAS..10113648E . free .
3. Kamnasaran D, Muir WJ, Ferguson-Smith MA, Cox DW . Disruption of the neuronal PAS3 gene in a family affected with schizophrenia . Journal of Medical Genetics . 40 . 5 . 325–32 . May 2003 . 12746393 . 1735455 . 10.1136/jmg.40.5.325 .
4. Pickard BS, Malloy MP, Porteous DJ, Blackwood DH, Muir WJ . 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 . Jul 2005 . 15924306 . 10.1002/ajmg.b.30204 . 33879828 .
5. Pickard BS, Pieper AA, Porteous DJ, Blackwood DH, Muir WJ . The NPAS3 gene--emerging evidence for a role in psychiatric illness . Annals of Medicine . 38 . 6 . 439–48 . 2006 . 17008307 . 10.1080/07853890600946500 . free .
6. Pickard BS, Christoforou A, Thomson PA, Fawkes A, Evans KL, Morris SW, Porteous DJ, Blackwood DH, Muir WJ . Interacting haplotypes at the NPAS3 locus alter risk of schizophrenia and bipolar disorder . Molecular Psychiatry . 14 . 9 . 874–84 . Sep 2009 . 18317462 . 10.1038/mp.2008.24 . free .
7. Lavedan C, Volpi S, Mack K, et al. Whole-genome association study identifies polymorphisms in the NPAS3 gene associated with super-response to iloperidone treatment in patients with schizophrenia. Program and abstracts of the 57th Annual Meeting of the American Society of Human Genetics; October 23–27, 2007; San Diego, California. Abstract 1035/T