Neurodevelopmental defects in human cortical organoids with <i>N</i>-acetylneuraminic acid synthase mutation.

Abstract

Biallelic genetic variants in <i>N</i>-acetylneuraminic acid synthase (<i>NANS</i>), 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 <i>NANS</i> 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. <i>NANS</i> mutation dysregulated neural migration and differentiation, disturbed synapse formation, and weakened neuronal activity. Single-cell RNA sequencing revealed that <i>NANS</i> loss of function markedly altered transcriptional programs involved in neuronal differentiation and ribosomal biogenesis in various neuronal cell types. Similarly, <i>Nans</i> 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 <i>NANS</i> mutation with its clinically relevant neurodevelopmental disorders.