NANS, encoding the synthase for N-acetylneuraminic acid (NeuNAc; sialic acid), is an essential enzyme in the de novo sialic acid synthesis pathway. Sialic acid at the end of glycoconjugates is crucial for biological processes like brain and skeletal development [1,2].

Biallelic mutations in NANS have been identified in individuals with infantile-onset severe developmental delay and skeletal dysplasia. Patient-derived fibroblasts had reduced NANS activity and impaired sialic acid incorporation into sialylated glycoproteins [2]. Knockdown of nansa in zebrafish embryos led to abnormal skeletal development, which was partially rescued by exogenously added sialic acid [2]. In human cortical organoids, NANS mutation caused absence of sialic acid and protein polysialylation, reduced neural progenitor proliferation, and dysregulated neural migration, differentiation, synapse formation, and neuronal activity. Nans heterozygous mice also showed impaired cortical neurogenesis and neurobehavioral deficits [3].

In conclusion, NANS-mediated synthesis of sialic acid is required for early brain development and skeletal growth. Studies using model organisms like zebrafish embryos and mice have revealed its role in these processes, and its deficiency is associated with neurodevelopmental and skeletal disorders [2,3].

References:

1. den Hollander, Bibiche, Rasing, Anne, Post, Merel A, Lefeber, Dirk J, van Karnebeek, Clara D M. 2021. NANS-CDG: Delineation of the Genetic, Biochemical, and Clinical Spectrum. In Frontiers in neurology, 12, 668640. doi:10.3389/fneur.2021.668640. https://pubmed.ncbi.nlm.nih.gov/34163424/

2. van Karnebeek, Clara D M, Bonafé, Luisa, Wen, Xiao-Yan, Wevers, Ron A, Superti-Furga, Andrea. 2016. NANS-mediated synthesis of sialic acid is required for brain and skeletal development. In Nature genetics, 48, 777-84. doi:10.1038/ng.3578. https://pubmed.ncbi.nlm.nih.gov/27213289/

3. Bu, Qian, Dai, Yanping, Zhang, Huaqin, Zhao, Yinglan, Cen, Xiaobo. 2023. Neurodevelopmental defects in human cortical organoids with N-acetylneuraminic acid synthase mutation. In Science advances, 9, eadf2772. doi:10.1126/sciadv.adf2772. https://pubmed.ncbi.nlm.nih.gov/38000033/