Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/90665
Citations
Scopus Web of Science® Altmetric
?
?
Type: Journal article
Title: Human variants in the Neuronal Basic Helix-Loop-Helix/ Per-Arnt-Sim (bHLH/PAS) transcription factor complex NPAS4/ARNT2 disrupt function
Author: Bersten, D.
Bruning, J.
Peet, D.
Whitelaw, M.
Citation: PLoS One, 2014; 9(1):e85768-1-e85768-11
Publisher: Public Library of Science
Issue Date: 2014
ISSN: 1932-6203
1932-6203
Statement of
Responsibility: 
David C. Bersten, John B. Bruning, Daniel J. Peet, Murray L. Whitelaw
Abstract: Neuronal Per-Arnt-Sim homology (PAS) Factor 4 (NPAS4) is a neuronal activity-dependent transcription factor which heterodimerises with ARNT2 to regulate genes involved in inhibitory synapse formation. NPAS4 functions to maintain excitatory/inhibitory balance in neurons, while mouse models have shown it to play roles in memory formation, social interaction and neurodegeneration. NPAS4 has therefore been implicated in a number of neuropsychiatric or neurodegenerative diseases which are underpinned by defects in excitatory/inhibitory balance. Here we have explored a broad set of non-synonymous human variants in NPAS4 and ARNT2 for disruption of NPAS4 function. We found two variants in NPAS4 (F147S and E257K) and two variants in ARNT2 (R46W and R107H) which significantly reduced transcriptional activity of the heterodimer on a luciferase reporter gene. Furthermore, we found that NPAS4.F147S was unable to activate expression of the NPAS4 target gene BDNF due to reduced dimerisation with ARNT2. Homology modelling predicts F147 in NPAS4 to lie at the dimer interface, where it appears to directly contribute to protein/protein interaction. We also found that reduced transcriptional activation by ARNT2 R46W was due to disruption of nuclear localisation. These results provide insight into the mechanisms of NPAS4/ARNT dimerisation and transcriptional activation and have potential implications for cognitive phenotypic variation and diseases such as autism, schizophrenia and dementia.
Keywords: Cell Nucleus; Animals; Humans; Mice; Brain-Derived Neurotrophic Factor; Phenylalanine; Repressor Proteins; Amino Acid Sequence; Structural Homology, Protein; Protein Transport; Mutation; Genes, Reporter; Models, Molecular; Molecular Sequence Data; Mutant Proteins; Aryl Hydrocarbon Receptor Nuclear Translocator; Basic Helix-Loop-Helix Transcription Factors; Protein Multimerization; HEK293 Cells
Rights: © 2014 Bersten et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
RMID: 0030009347
DOI: 10.1371/journal.pone.0085768
Appears in Collections:Agriculture, Food and Wine publications

Files in This Item:
File Description SizeFormat 
hdl_90665.pdfPublished version1.61 MBAdobe PDFView/Open


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.