NANS-mediated synthesis of sialic acid is required for brain and skeletal development

Nat Genet. 2016 Jul;48(7):777-84. doi: 10.1038/ng.3578. Epub 2016 May 23.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Animals
  • Bone Diseases, Developmental / genetics
  • Bone Diseases, Developmental / metabolism
  • Bone Diseases, Developmental / pathology*
  • Brain / embryology*
  • Brain / metabolism
  • Brain / pathology
  • Child, Preschool
  • Developmental Disabilities / genetics
  • Developmental Disabilities / metabolism
  • Developmental Disabilities / pathology*
  • Embryo, Nonmammalian / metabolism
  • Embryo, Nonmammalian / pathology
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Metabolism, Inborn Errors / genetics
  • Metabolism, Inborn Errors / metabolism
  • Metabolism, Inborn Errors / pathology
  • Mutation / genetics*
  • Oxo-Acid-Lyases / genetics*
  • Sialic Acids / metabolism*
  • Zebrafish / embryology*
  • Zebrafish / genetics
  • Zebrafish / metabolism

Substances

  • Sialic Acids
  • N-acylneuraminate-9-phosphate synthase
  • Oxo-Acid-Lyases

Grants and funding