2. Academic Validation
  3. NANS-mediated synthesis of sialic acid is required for brain and skeletal development

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.
Clara D M van Karnebeek 1 2,  Luisa Bonafé 3,  Xiao-Yan Wen 4 5,  Maja Tarailo-Graovac 2 6,  Sara Balzano 7,  Beryl Royer-Bertrand 3 7,  Angel Ashikov 8,  Livia Garavelli 9,  Isabella Mammi 10,  Licia Turolla 11,  Catherine Breen 12,  Dian Donnai 12,  Valérie Cormier-Daire 13,  Delphine Heron 10,  Gen Nishimura 14,  Shinichi Uchikawa 15,  Belinda Campos-Xavier 3,  Antonio Rossi 16,  Thierry Hennet 17,  Koroboshka Brand-Arzamendi 4 5,  Jacob Rozmus 1,  Keith Harshman 18,  Brian J Stevenson 19,  Enrico Girardi 20,  Giulio Superti-Furga 20 21,  Tammie Dewan 1,  Alissa Collingridge 1,  Jessie Halparin 1,  Colin J Ross 1 2 6,  Margot I Van Allen 6,  Andrea Rossi 22,  Udo F Engelke 23,  Leo A J Kluijtmans 23,  Ed van der Heeft 23,  Herma Renkema 23,  Arjan de Brouwer 24,  Karin Huijben 23,  Fokje Zijlstra 23,  Torben Heise 25,  Thomas Boltje 25,  Wyeth W Wasserman 2 6,  Carlo Rivolta 7,  Sheila Unger 26,  Dirk J Lefeber 8 23,  Ron A Wevers 23,  Andrea Superti-Furga 3 27
Affiliations

Affiliations

  • 1 Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.
  • 2 Centre for Molecular Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
  • 3 Centre for Molecular Diseases, Lausanne University Hospital (CHUV), University of Lausanne, Lausanne, Switzerland.
  • 4 Zebrafish Centre for Advanced Drug Discovery, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
  • 5 Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
  • 6 Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
  • 7 Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
  • 8 Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 9 Clinical Genetics Unit, IRCCS-S. Maria Nuova Hospital, Reggio Emilia, Italy.
  • 10 Ambulatorio di Genetica Medica ULSS 13, U.O. Ginecologia e Ostetricia, Ospedale Dolo, Dolo, Italy.
  • 11 Medical Genetics Unit, Local Health Authority (ULSS 9), Treviso, Italy.
  • 12 Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
  • 13 Institut IMAGINE, Hôpital Necker-Enfants Malades, Paris, France.
  • 14 Department of Radiology, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.
  • 15 Department of Orthopedics, National Center for Child Health and Development, Tokyo, Japan.
  • 16 Department of Molecular Medicine, Unit of Biochemistry, University of Pavia, Pavia, Italy.
  • 17 Department of Physiology, University of Zürich, Zurich, Switzerland.
  • 18 Genomic Technologies Facility, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
  • 19 Vital-IT Group, Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland.
  • 20 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • 21 Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
  • 22 Neuroradiology Department, G. Gaslini Children's Hospital, Genoa, Italy.
  • 23 Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 24 Department of Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 25 Department of Organic Chemistry, Radboud University, Nijmegen, the Netherlands.
  • 26 Medical Genetics Service, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
  • 27 Department of Pediatrics, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
PMID: 27213289 DOI: 10.1038/ng.3578
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.

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