Molecular characterisation of rare loss-of-function NPAS3 and NPAS4 variants identified in individuals with neurodevelopmental disorders
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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.
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NPAS3 and NPAS4 are implicated in controlling the excitatory/inhibitory synapse balance throughout the brain, and targeted disruption of either gene in mice results in a phenotype resembling intellectual disability and schizophrenia.
“More recently, NPAS3 and its paralog NPAS4 have been implicated in controlling the excitatory/inhibitory synapse balance throughout the brain, and targeted disruption of either gene in mice results in a phenotype resembling intellectual disability and schizophrenia (Rossi et al. 2021).”
From The Human Accelerated Region HAR202 Controls <i>NPAS3</i> Expression in the Developing Forebrain Displaying Differential Enhancer Activity Between Modern and Archaic Human Sequences (2024) · cites this paper as Rossi et al. 2021
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Sun, X., Jing, L., Li, F., Zhang, M., Diao, X., Zhuang, J., Rastinejad, F., & Wu, D. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2208804119 · Cited by 32 · see citing works
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“More recently, NPAS3 and its paralog NPAS4 have been implicated in controlling the excitatory/inhibitory synapse balance throughout the brain, and targeted disruption of either gene in mice results in a phenotype resembling intellectual disability and schizophrenia ( Rossi et al. 2021).”
Background
- Authors
- Rossi, J. J., Rosenfeld, J. A., Chan, K. M., Streff, H., Nankivell, V., Peet, D. J., Whitelaw, M. L., & Bersten, D. C.
- Affiliations
- The University of Adelaide (AU)
- Baylor College of Medicine (US)
- Corresponding author
- Bersten, David C.
- ORCID
- Venue
- Scientific Reports
- Published
- 2021-03-23
- Volume
- 11
- Issue
- 1
- Pages
- 6602-6602
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC7987981
- OpenAlex
- W3137941169
- Cited by
- 17
- References
- 72
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 5 · 2023: 4 · 2022: 1 · 2021: 1
- FWCI
- 1.55
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- NPAS3, Npas4, loss-of-function mutations, neurodevelopmental disorders, intellectual disability, developmental delay, excitation-inhibition balance, bHLH-PAS transcription factors, ARNT2, transcriptional activity, schizophrenia, candidate genes
- MeSH terms
- Loss of Function Mutation, Developmental Disabilities, Humans, Protein Binding, Aryl Hydrocarbon Receptor Nuclear Translocator, Basic Helix-Loop-Helix Proteins, HEK293 Cells
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