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


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

Authors Bu Q, Dai Y, Zhang H, Li M, Liu H, Huang Y, Zeng A, Qin F, Jiang L, Wang L, Chen Y, Li H, Wang X, Zhao Y, Qin M, Zhao Y, Zhang N, Kuang W, Zhao Y, Cen X
Journal Science advances
Publication Date 2023 Nov 24;9(47):eadf2772
PubMed 38000033
PubMed Central PMC10672180
DOI 10.1126/sciadv.adf2772

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