Relevance to Autism

Chen et al., 2025 integrated cortex cell-specific cis-regulatory element annotations, a deep learning-based variant prediction model, and massively parallel reporter assays to systematically evaluate the functional impact of 227,878 non-coding de novo mutations (ncDNMs) in ASD probands from Simons Simplex Collection (SSC) and Autism Speaks MSSNG resource (MSSNG) cohorts and identified a ncDNM that down-regulated expression of the NPAS3 gene in a SSC proband. Additional de novo variants, including a loss-of-function variant and two missense variants, have been identified in the NPAS3 gene in ASD probands (De Rubeis et al., 2014; Satterstrom et al., 2020; Fu et al., 2022; Trost et al., 2022). Li et al., 2022 found that Npas3deficiency in mice resulted in impaired cortical astrogenesis, which correlated with abnormal brain development and autistic-like behaviors. Michaelson et al., 2017 found that Fmr1 and Ube3a were transcriptionally regulated by NPAS3, as was the neurogenesis regulator Notch. Rare coding variants in NPAS3, including a frameshift variant that was experimentally shown to result in loss of transcriptional activity, had been previously reported in individuals with NDDs from the Baylor Genetics clinical exome sequencing database in Rossi et al., 2021.

Molecular Function

This gene encodes a member of the basic helix-loop-helix and PAS domain-containing family of transcription factors. The encoded protein is localized to the nucleus and may regulate genes involved in neurogenesis. Chromosomal abnormalities that affect the coding potential of this gene are associated with schizophrenia and cognitive disability.

External Links

References