ESC derived human cortical neurons harboring the NACC1 c.892C > T p.R298W missense mutation exhibit molecular differences from controls that influence neuronal maturation.

A de novo mutation in the transcription factor Nucleus accumbens associated protein 1 (NACC1) gene (c.892C > T p.R298W) causes a rare, severe neurodevelopmental disorder which manifests postnatally. Genome editing was used to generate human isogenic ESCs (control, mutant heterozygote and homozygote lines) which were differentiated to cortical neurons. Mutant neurons expressed higher levels of NACC1 protein by western blot. RNAseq, GO term and SynGO analysis revealed altered expression of transcripts involved with pre- and postsynaptic signaling, neurotransmission, extracellular matrix, and adhesion. Western blot revealed increased expression of the presynaptic proteins SNAP25 and VAMP2 and the postsynaptic protein SYNGAP1. A functional assay showed increased adhesion of neural stem cells to collagen 1 and 4. The mutation also changed levels of transcripts measured by qPCR involved with dorsal ventral patterning to favor a ventral signature. These results suggest that the NACC1 R298W mutation causes molecular changes in an embryonic cell model that may impact postnatal development of cortical neurons.