Molecular characterisation of rare loss-of-function NPAS3 and NPAS4 variants identified in individuals with neurodevelopmental disorders

Abstract Aberrations in the excitatory/inhibitory balance within the brain have been associated with both intellectual disability (ID) and schizophrenia (SZ). The bHLH-PAS transcription factors NPAS3 and NPAS4 have been implicated in controlling the excitatory/inhibitory balance, and targeted disrup...

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Autores principales:	Joseph J. Rossi, Jill A. Rosenfeld, Katie M. Chan, Haley Streff, Victoria Nankivell, Daniel J. Peet, Murray L. Whitelaw, David C. Bersten
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/73dc68bd23a646a9be57617e8f6d2c2a
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spelling	oai:doaj.org-article:73dc68bd23a646a9be57617e8f6d2c2a2021-12-02T17:04:35ZMolecular characterisation of rare loss-of-function NPAS3 and NPAS4 variants identified in individuals with neurodevelopmental disorders10.1038/s41598-021-86041-42045-2322https://doaj.org/article/73dc68bd23a646a9be57617e8f6d2c2a2021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-86041-4https://doaj.org/toc/2045-2322Abstract Aberrations in the excitatory/inhibitory balance within the brain have been associated with both intellectual disability (ID) and schizophrenia (SZ). The bHLH-PAS transcription factors NPAS3 and NPAS4 have been implicated in controlling the excitatory/inhibitory balance, and targeted disruption of either gene in mice results in a phenotype resembling ID and SZ. However, there are few human variants in NPAS3 and none in NPAS4 that have been associated with schizophrenia or neurodevelopmental disorders. From a clinical exome sequencing database we identified three NPAS3 variants and four NPAS4 variants that could potentially disrupt protein function in individuals with either developmental delay or ID. The transcriptional activity of the variants when partnered with either ARNT or ARNT2 was assessed by reporter gene activity and it was found that variants which truncated the NPAS3/4 protein resulted in a complete loss of transcriptional activity. The ability of loss-of-function variants to heterodimerise with neuronally enriched partner protein ARNT2 was then determined by co-immunoprecipitation experiments. It was determined that the mechanism for the observed loss of function was the inability of the truncated NPAS3/4 protein to heterodimerise with ARNT2. This further establishes NPAS3 and NPAS4 as candidate neurodevelopmental disorder genes.Joseph J. RossiJill A. RosenfeldKatie M. ChanHaley StreffVictoria NankivellDaniel J. PeetMurray L. WhitelawDavid C. BerstenNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Joseph J. Rossi Jill A. Rosenfeld Katie M. Chan Haley Streff Victoria Nankivell Daniel J. Peet Murray L. Whitelaw David C. Bersten Molecular characterisation of rare loss-of-function NPAS3 and NPAS4 variants identified in individuals with neurodevelopmental disorders
description	Abstract Aberrations in the excitatory/inhibitory balance within the brain have been associated with both intellectual disability (ID) and schizophrenia (SZ). The bHLH-PAS transcription factors NPAS3 and NPAS4 have been implicated in controlling the excitatory/inhibitory balance, and targeted disruption of either gene in mice results in a phenotype resembling ID and SZ. However, there are few human variants in NPAS3 and none in NPAS4 that have been associated with schizophrenia or neurodevelopmental disorders. From a clinical exome sequencing database we identified three NPAS3 variants and four NPAS4 variants that could potentially disrupt protein function in individuals with either developmental delay or ID. The transcriptional activity of the variants when partnered with either ARNT or ARNT2 was assessed by reporter gene activity and it was found that variants which truncated the NPAS3/4 protein resulted in a complete loss of transcriptional activity. The ability of loss-of-function variants to heterodimerise with neuronally enriched partner protein ARNT2 was then determined by co-immunoprecipitation experiments. It was determined that the mechanism for the observed loss of function was the inability of the truncated NPAS3/4 protein to heterodimerise with ARNT2. This further establishes NPAS3 and NPAS4 as candidate neurodevelopmental disorder genes.
format	article
author	Joseph J. Rossi Jill A. Rosenfeld Katie M. Chan Haley Streff Victoria Nankivell Daniel J. Peet Murray L. Whitelaw David C. Bersten
author_facet	Joseph J. Rossi Jill A. Rosenfeld Katie M. Chan Haley Streff Victoria Nankivell Daniel J. Peet Murray L. Whitelaw David C. Bersten
author_sort	Joseph J. Rossi
title	Molecular characterisation of rare loss-of-function NPAS3 and NPAS4 variants identified in individuals with neurodevelopmental disorders
title_short	Molecular characterisation of rare loss-of-function NPAS3 and NPAS4 variants identified in individuals with neurodevelopmental disorders
title_full	Molecular characterisation of rare loss-of-function NPAS3 and NPAS4 variants identified in individuals with neurodevelopmental disorders
title_fullStr	Molecular characterisation of rare loss-of-function NPAS3 and NPAS4 variants identified in individuals with neurodevelopmental disorders
title_full_unstemmed	Molecular characterisation of rare loss-of-function NPAS3 and NPAS4 variants identified in individuals with neurodevelopmental disorders
title_sort	molecular characterisation of rare loss-of-function npas3 and npas4 variants identified in individuals with neurodevelopmental disorders
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/73dc68bd23a646a9be57617e8f6d2c2a
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Molecular characterisation of rare loss-of-function NPAS3 and NPAS4 variants identified in individuals with neurodevelopmental disorders

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