Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/90665
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dc.contributor.authorBersten, D.en
dc.contributor.authorBruning, J.en
dc.contributor.authorPeet, D.en
dc.contributor.authorWhitelaw, M.en
dc.date.issued2014en
dc.identifier.citationPLoS One, 2014; 9(1):e85768-1-e85768-11en
dc.identifier.issn1932-6203en
dc.identifier.issn1932-6203en
dc.identifier.urihttp://hdl.handle.net/2440/90665-
dc.description.abstractNeuronal 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.en
dc.description.statementofresponsibilityDavid C. Bersten, John B. Bruning, Daniel J. Peet, Murray L. Whitelawen
dc.language.isoenen
dc.publisherPublic Library of Scienceen
dc.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.en
dc.subjectCell 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 Cellsen
dc.titleHuman variants in the Neuronal Basic Helix-Loop-Helix/ Per-Arnt-Sim (bHLH/PAS) transcription factor complex NPAS4/ARNT2 disrupt functionen
dc.typeJournal articleen
dc.identifier.rmid0030009347en
dc.identifier.doi10.1371/journal.pone.0085768en
dc.identifier.pubid84020-
pubs.library.collectionAgriculture, Food and Wine publicationsen
pubs.library.teamDS05en
pubs.verification-statusVerifieden
pubs.publication-statusPublisheden
Appears in Collections:Agriculture, Food and Wine publications

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