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

C. Van Karnebeek, Luisa Bonafé, Xiao Yan Wen, Maja Tarailo-Graovac, Sara Balzano, Beryl Royer-Bertrand, Angel Ashikov, Livia Garavelli, Isabella Mammi, Licia Turolla, Catherine Breen, Dian Donnai, Valerie Cormier, Délphine Heron, Gen Nishimura, Shinichi Uchikawa, Belinda Campos-Xavier, Antonio Rossi, T. Hennet, Koroboshka Brand-ArzamendiJacob Rozmus, Keith Harshman, Brian Stevenson, Enrico Girardi, Giulio Superti-Furga, Tammie Dewan, Alissa Collingridge, Jessie Halparin, Colin J. Ross, Margot Van Allen, Andrea Rossi, Udo Engelke, Leo A J Kluijtmans, Ed Van Der Heeft, Herma Renkema, Arjan P. De Brouwer, Karin Huijben, Fokje Zijlstra, Thorben Heisse, Thomas Boltje, Wyeth W. Wasserman, Carlo Rivolta, Sheila Unger, Dirk J. Lefeber, Ron A. Wevers, Andrea Superti-Furga

Research output: Contribution to journalArticle


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.

Original languageEnglish
Pages (from-to)777-784
Number of pages8
JournalNature Genetics
Issue number7
Publication statusPublished - Jul 1 2016


ASJC Scopus subject areas

  • Medicine(all)
  • Genetics

Cite this

Van Karnebeek, C., Bonafé, L., Wen, X. Y., Tarailo-Graovac, M., Balzano, S., Royer-Bertrand, B., Ashikov, A., Garavelli, L., Mammi, I., Turolla, L., Breen, C., Donnai, D., Cormier, V., Heron, D., Nishimura, G., Uchikawa, S., Campos-Xavier, B., Rossi, A., Hennet, T., ... Superti-Furga, A. (2016). NANS-mediated synthesis of sialic acid is required for brain and skeletal development. Nature Genetics, 48(7), 777-784.