• A Corrigendum to this article was published on 26 May 2017

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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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Change history

  • 06 March 2017

    In the version of this article initially published, the name of author Torben Heise was given incorrectly as Thorben Heisse, and the name of author Valérie Cormier-Daire was given incorrectly as Valerie Cormier. The institutional affiliation for Delphine Heron was listed incorrectly as Institut IMAGINE, Hôpital Necker–Enfants Malades, Paris, France, and should have been listed as Département de Génétique Médicale et Centre de Référence Déficiences Intellectuelles, Groupe Hospitalier Pitié-Salpêtrière, Université Pierre et Marie Curie, Paris, France. The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank M. Filocamo at the Gaslini Biobank (Genoa, Italy) for a fibroblast line for patient 1. We thank A. Reymond (CIG, FBM, Université de Lausanne) and his laboratory for lymphocyte immortalization. We thank C. Chiesa for Sanger sequencing and sample handling and shipment; S. de Boer for excellent technical assistance; B. Toh at the University of British Columbia for metabolic sample handling; X. Han for Sanger sequencing; B. Sayson for consenting and data management; M. Higginson for DNA extraction and sample handling; and A. Ghani for administrative assistance. We also thank R. Houben for skillfully preparing Figure 4 and A. Bandi for all other figures. We are grateful to our clinical colleagues in Dolo, Genoa, Lausanne, Manchester, Paris, Reggio Emilia, Tokyo, Treviso, and Vancouver for patient management. A.S.-F. dedicates this paper to the memory of Paolo Durand who pointed out the relationship between sialic acid metabolism and IDD to him in 1980. Finally, we wish to thank the patients reported here as well as their parents for the enthusiasm they showed for our research efforts, for their patience, which was challenged by the studies lasting many years, and for their repeated donation of biological samples. They have been the source of continuous motivation for us.

This work has been supported by funding from the Leenaards Foundation in Lausanne, Switzerland; the Faculty of Biology and Medicine of the University of Lausanne; the BC Children's Hospital Foundation (Treatable Intellectual Disability Endeavour in British Columbia: First Collaborative Area of Innovation); Genome BC (grant SOF-195); the Rare Diseases Foundation; the Rare Diseases Models and Mechanisms Network; the Canadian Institutes of Health Research (grant 301221); and the Dutch Organization for Scientific Research, ZONMW (Medium Investment Grant 40-00506-98-9001 and VIDI Grant 91713359 to D.J.L.). The zebrafish studies were supported by funding to X.-Y.W. from the Canadian Rare Disease Models and Mechanisms Network, the Brain Canada Foundation, the Natural Sciences and Engineering Research Council of Canada (NSERC), and the Canada Foundation for Innovation (CFI). The informatics infrastructures were supported by Genome BC and Genome Canada (ABC4DE Project) as well as by the Vital-IT Project of the Swiss Institute of Bioinformatics (SIB; Lausanne, Switzerland). C.J.R. is funded by a Canadian Institutes of Health Research New Investigator Award. C.D.M.v.K. is a recipient of the Michael Smith Foundation for Health Research Scholar Award (Vancouver, Canada). E.G. is supported by a Marie Skłodowska-Curie fellowship (MSCA-IF-661491).

Author information

Author notes

    • Clara D M van Karnebeek
    • , Luisa Bonafé
    •  & Xiao-Yan Wen

    These authors contributed equally to this work.

    • Ron A Wevers
    •  & Andrea Superti-Furga

    These authors jointly supervised this work.

Affiliations

  1. Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.

    • Clara D M van Karnebeek
    • , Jacob Rozmus
    • , Tammie Dewan
    • , Alissa Collingridge
    • , Jessie Halparin
    •  & Colin J Ross
  2. Centre for Molecular Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.

    • Clara D M van Karnebeek
    • , Maja Tarailo-Graovac
    • , Colin J Ross
    •  & Wyeth W Wasserman
  3. Centre for Molecular Diseases, Lausanne University Hospital (CHUV), University of Lausanne, Lausanne, Switzerland.

    • Luisa Bonafé
    • , Beryl Royer-Bertrand
    • , Belinda Campos-Xavier
    •  & Andrea Superti-Furga
  4. Zebrafish Centre for Advanced Drug Discovery, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.

    • Xiao-Yan Wen
    •  & Koroboshka Brand-Arzamendi
  5. Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

    • Xiao-Yan Wen
    •  & Koroboshka Brand-Arzamendi
  6. Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.

    • Maja Tarailo-Graovac
    • , Colin J Ross
    • , Margot I Van Allen
    •  & Wyeth W Wasserman
  7. Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.

    • Sara Balzano
    • , Beryl Royer-Bertrand
    •  & Carlo Rivolta
  8. Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.

    • Angel Ashikov
    •  & Dirk J Lefeber
  9. Clinical Genetics Unit, IRCCS-S. Maria Nuova Hospital, Reggio Emilia, Italy.

    • Livia Garavelli
  10. Ambulatorio di Genetica Medica ULSS 13, U.O. Ginecologia e Ostetricia, Ospedale Dolo, Dolo, Italy.

    • Isabella Mammi
  11. Medical Genetics Unit, Local Health Authority (ULSS 9), Treviso, Italy.

    • Licia Turolla
  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.

    • Catherine Breen
    •  & Dian Donnai
  13. Institut IMAGINE, Hôpital Necker–Enfants Malades, Paris, France.

    • Valérie Cormier-Daire
  14. Department of Radiology, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.

    • Gen Nishimura
  15. Department of Orthopedics, National Center for Child Health and Development, Tokyo, Japan.

    • Shinichi Uchikawa
  16. Department of Molecular Medicine, Unit of Biochemistry, University of Pavia, Pavia, Italy.

    • Antonio Rossi
  17. Department of Physiology, University of Zürich, Zurich, Switzerland.

    • Thierry Hennet
  18. Genomic Technologies Facility, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.

    • Keith Harshman
  19. Vital-IT Group, Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland.

    • Brian J Stevenson
  20. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

    • Enrico Girardi
    •  & Giulio Superti-Furga
  21. Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.

    • Giulio Superti-Furga
  22. Neuroradiology Department, G. Gaslini Children's Hospital, Genoa, Italy.

    • Andrea Rossi
  23. Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.

    • Udo F Engelke
    • , Leo A J Kluijtmans
    • , Ed van der Heeft
    • , Herma Renkema
    • , Karin Huijben
    • , Fokje Zijlstra
    • , Dirk J Lefeber
    •  & Ron A Wevers
  24. Department of Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.

    • Arjan de Brouwer
  25. Department of Organic Chemistry, Radboud University, Nijmegen, the Netherlands.

    • Torben Heise
    •  & Thomas Boltje
  26. Medical Genetics Service, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.

    • Sheila Unger
  27. Department of Pediatrics, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.

    • Andrea Superti-Furga
  28. Département de Génétique Médicale et Centre de Référence Déficiences Intellectuelles, Groupe Hospitalier Pitié-Salpêtrière, Université Pierre et Marie Curie, Paris, France.

    • Delphine Heron

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Contributions

C.D.M.v.K., L.B., S. Unger, R.A.W., and A.S.-F. conceived the study and coordinated and supervised the different teams. A.S.-F., L.B., C.D.M.v.K., T.D., A.C., M.I.V.A., C.J.R., J.H., L.G., L.T., V.C.-D., D.H., D.D., C.B., I.M., and S. Uchikawa recruited the patients, reviewed the clinical and radiographic features, and obtained biological materials from patients. A.S.-F., S. Unger, and G.N. reviewed the radiographic data. J.R. performed the bone marrow studies. Andrea Rossi reviewed the cerebral imaging. K. Harshman, B.J.S., B.C.-X., S.B., B.R.-B., H.R., C.R., M.T.-G., W.W.W., and A.d.B. were responsible for exome sequencing, haplotype reconstruction, Sanger sequencing, database studies, and mRNA–cDNA studies. R.A.W., L.A.J.K., E.v.d.H., and U.F.E. performed the metabolomics studies. Antonio Rossi studied ManNAc incorporation in fibroblasts. T. Hennet performed the lectin binding studies. A.A., K. Huijben, F.Z., and D.J.L. performed the NANS enzyme assays. D.J.L., A.A., T. Heisse, and T.B. studied the incorporation of sialic acid precursors in lymphocytes and fibroblasts. E.G. and G.S.-F. obtained the NANS three-dimensional model and mapped the affected amino acid residues. X.-Y.W. and K.B.-A. generated and phenotyped the zebrafish model. C.D.M.v.K. and A.S.-F. prepared the manuscript with contributions from all co-authors. All co-authors edited and reviewed the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Clara D M van Karnebeek or Ron A Wevers or Andrea Superti-Furga.

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https://doi.org/10.1038/ng.3578

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