2016/05/23 by Clara van Karnebeek, Luisa Bonafé, Xiao‐Yan Wen +43 · 1 citation
Biochemistry, Genetics and Molecular Biology · Nursing · #Glycosylation and Glycoproteins Research #Infant Nutrition and Health #RNA modifications and cancer
paper · pdf · doi:10.1038/ng.3578
openalex publication_date 2016/05/23 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
Andrea Superti-Furga, Ron Wevers, Clara van Karnebeek, Luisa Bonafé and colleagues identify mutations in NANS, which encodes the sialic acid synthase, in nine individuals with severe infantile-onset developmental delay and skeletal dysplasia. They describe abnormal metabolites accumulating because of deficient NANS enzyme activity and show that impaired sialic acid synthesis in zebrafish perturbs skeletal development, which can partially be rescued by supplementation with exogenous sialic acid. We identified biallelic mutations in NANS, the gene encoding the synthase for N-acetylneuraminic acid (NeuNAc; sialic acid), in nine individuals with infantile-onset severe developmental delay and skeletal dysplasia. Patient body fluids showed an elevation in N-acetyl-D-mannosamine levels, and patient-derived fibroblasts had reduced NANS activity and were unable to incorporate sialic acid precursors into sialylated glycoproteins. Knockdown of nansa in zebrafish embryos resulted in abnormal skeletal development, and exogenously added sialic acid partially rescued the skeletal phenotype. Thus, NANS-mediated synthesis of sialic acid is required for early brain development and skeletal growth. Normal sialylation of plasma proteins was observed in spite of NANS deficiency. Exploration of endogenous synthesis, nutritional absorption, and rescue pathways for sialic acid in different tissues and developmental phases is warranted to design therapeutic strategies to counteract NANS deficiency and to shed light on sialic acid metabolism and its implications for human nutrition.