title: NANS-mediated synthesis of sialic acid is required for brain and skeletal development.
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.
authors.affiliation: Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.|Centre for Molecular Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Clara D M
authors.initials: CD
authors.lastname: van Karnebeek
authors.affiliation: Centre for Molecular Diseases, Lausanne University Hospital (CHUV), University of Lausanne, Lausanne, Switzerland.
authors.forename: Luisa
authors.initials: L
authors.lastname: Bonafé
authors.affiliation: Zebrafish Centre for Advanced Drug Discovery, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.|Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Wen
authors.affiliation: Centre for Molecular Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Maja
authors.initials: M
authors.lastname: Tarailo-Graovac
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Sara
authors.initials: S
authors.lastname: Balzano
authors.affiliation: Centre for Molecular Diseases, Lausanne University Hospital (CHUV), University of Lausanne, Lausanne, Switzerland.|Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Beryl
authors.initials: B
authors.lastname: Royer-Bertrand
authors.affiliation: Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Angel
authors.initials: A
authors.lastname: Ashikov
authors.affiliation: Clinical Genetics Unit, IRCCS-S. Maria Nuova Hospital, Reggio Emilia, Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Garavelli
authors.affiliation: Ambulatorio di Genetica Medica ULSS 13, U.O. Ginecologia e Ostetricia, Ospedale Dolo, Dolo, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Mammi
authors.affiliation: Medical Genetics Unit, Local Health Authority (ULSS 9), Treviso, Italy.
authors.forename: Licia
authors.initials: L
authors.lastname: Turolla
authors.affiliation: 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.
authors.forename: Catherine
authors.initials: C
authors.lastname: Breen
authors.affiliation: 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.
authors.forename: Dian
authors.initials: D
authors.lastname: Donnai
authors.affiliation: Institut IMAGINE, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
authors.affiliation: Ambulatorio di Genetica Medica ULSS 13, U.O. Ginecologia e Ostetricia, Ospedale Dolo, Dolo, Italy.
authors.forename: Delphine
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authors.affiliation: Department of Radiology, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.
authors.forename: Gen
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authors.affiliation: Department of Orthopedics, National Center for Child Health and Development, Tokyo, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Uchikawa
authors.affiliation: Centre for Molecular Diseases, Lausanne University Hospital (CHUV), University of Lausanne, Lausanne, Switzerland.
authors.forename: Belinda
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authors.affiliation: Department of Molecular Medicine, Unit of Biochemistry, University of Pavia, Pavia, Italy.
authors.forename: Antonio
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authors.affiliation: Department of Physiology, University of Zürich, Zurich, Switzerland.
authors.forename: Thierry
authors.initials: T
authors.lastname: Hennet
authors.affiliation: Zebrafish Centre for Advanced Drug Discovery, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.|Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Koroboshka
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authors.lastname: Brand-Arzamendi
authors.affiliation: Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jacob
authors.initials: J
authors.lastname: Rozmus
authors.affiliation: Genomic Technologies Facility, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
authors.forename: Keith
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authors.affiliation: Vital-IT Group, Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Brian J
authors.initials: BJ
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authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Enrico
authors.identifier: 0000-0003-3508-2723
authors.initials: E
authors.lastname: Girardi
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Giulio
authors.identifier: 0000-0002-0570-1768
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authors.affiliation: Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Tammie
authors.initials: T
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authors.affiliation: Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Alissa
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authors.affiliation: Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jessie
authors.initials: J
authors.lastname: Halparin
authors.affiliation: Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.|Centre for Molecular Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
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authors.initials: CJ
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authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
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authors.initials: MI
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authors.affiliation: Neuroradiology Department, G. Gaslini Children's Hospital, Genoa, Italy.
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authors.affiliation: Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Udo F
authors.initials: UF
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authors.affiliation: Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Leo A J
authors.initials: LA
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authors.affiliation: Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Ed
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authors.affiliation: Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Herma
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authors.affiliation: Department of Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Arjan
authors.initials: A
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authors.affiliation: Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Karin
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authors.affiliation: Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Fokje
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authors.affiliation: Department of Organic Chemistry, Radboud University, Nijmegen, the Netherlands.
authors.forename: Torben
authors.initials: T
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authors.affiliation: Department of Organic Chemistry, Radboud University, Nijmegen, the Netherlands.
authors.forename: Thomas
authors.initials: T
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authors.affiliation: Centre for Molecular Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Wyeth W
authors.initials: WW
authors.lastname: Wasserman
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Carlo
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authors.affiliation: Medical Genetics Service, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
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authors.initials: S
authors.lastname: Unger
authors.affiliation: Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.|Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Lefeber
authors.affiliation: Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
authors.affiliation: Centre for Molecular Diseases, Lausanne University Hospital (CHUV), University of Lausanne, Lausanne, Switzerland.|Department of Pediatrics, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
authors.forename: Andrea
authors.identifier: 0000-0002-3543-7531
authors.initials: A
authors.lastname: Superti-Furga
mesh_terms: D000328:Adult; D017668:Age of Onset; D000818:Animals; D001848:Bone Diseases, Developmental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D001921:Brain / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004625:Embryo, Nonmammalian / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008661:Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D007652:Oxo-Acid-Lyases / Q000235:genetics*; D012794:Sialic Acids / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics / Q000378:metabolism
chemical_list: D012794:Sialic Acids; C018767:N-acylneuraminate-9-phosphate synthase; D007652:Oxo-Acid-Lyases