Neurodevelopmental defects in human cortical organoids with -acetylneuraminic acid synthase mutation.

Biallelic genetic variants in -acetylneuraminic acid synthase (), a critical enzyme in endogenous sialic acid biosynthesis, are clinically associated with neurodevelopmental disorders. However, the mechanism underlying the neuropathological consequences has remained elusive. Here, we found that mutation resulted in the absence of both sialic acid and protein polysialylation in the cortical organoids and notably reduced the proliferation and expansion of neural progenitors. mutation dysregulated neural migration and differentiation, disturbed synapse formation, and weakened neuronal activity. Single-cell RNA sequencing revealed that loss of function markedly altered transcriptional programs involved in neuronal differentiation and ribosomal biogenesis in various neuronal cell types. Similarly, heterozygous mice exhibited impaired cortical neurogenesis and neurobehavioral deficits. Collectively, our findings reveal a crucial role of NANS-mediated endogenous sialic acid biosynthesis in regulating multiple features of human cortical development, thus linking mutation with its clinically relevant neurodevelopmental disorders.