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

doi:10.1038/ng.3578

. 2016 Jul;48(7):777-84.

doi: 10.1038/ng.3578. Epub 2016 May 23.

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

Clara D M van Karnebeek^{1

2}, Luisa Bonafé³, Xiao-Yan Wen^{4

5}, Maja Tarailo-Graovac^{2

6}, Sara Balzano⁷, Beryl Royer-Bertrand^{3

7}, Angel Ashikov⁸, Livia Garavelli⁹, Isabella Mammi¹⁰, Licia Turolla¹¹, Catherine Breen¹², Dian Donnai¹², Valérie Cormier-Daire¹³, Delphine Heron¹⁰, Gen Nishimura¹⁴, Shinichi Uchikawa¹⁵, Belinda Campos-Xavier³, Antonio Rossi¹⁶, Thierry Hennet¹⁷, Koroboshka Brand-Arzamendi^{4

5}, Jacob Rozmus¹, Keith Harshman¹⁸, Brian J Stevenson¹⁹, Enrico Girardi²⁰, Giulio Superti-Furga^{20

21}, Tammie Dewan¹, Alissa Collingridge¹, Jessie Halparin¹, Colin J Ross^{1

2

6}, Margot I Van Allen⁶, Andrea Rossi²², Udo F Engelke²³, Leo A J Kluijtmans²³, Ed van der Heeft²³, Herma Renkema²³, Arjan de Brouwer²⁴, Karin Huijben²³, Fokje Zijlstra²³, Torben Heise²⁵, Thomas Boltje²⁵, Wyeth W Wasserman^{2

6}, Carlo Rivolta⁷, Sheila Unger²⁶, Dirk J Lefeber^{8

23}, Ron A Wevers²³, Andrea Superti-Furga^{3

27}

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

Free article

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

Clara D M van Karnebeek et al. Nat Genet. 2016 Jul.

Free article

. 2016 Jul;48(7):777-84.

doi: 10.1038/ng.3578. Epub 2016 May 23.

Authors

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

Erratum in

Corrigendum: NANS-mediated synthesis of sialic acid is required for brain and skeletal development.
van Karnebeek CDM, Bonafé L, Wen XY, 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, Brand-Arzamendi K, Rozmus J, Harshman K, Stevenson BJ, Girardi E, Superti-Furga G, Dewan T, Collingridge A, Halparin J, Ross CJ, Van Allen MI, Rossi A, Engelke UF, Kluijtmans LAJ, van der Heeft E, Renkema H, de Brouwer A, Huijben K, Zijlstra F, Heisse T, Boltje T, Wasserman WW, Rivolta C, Unger S, Lefeber DJ, Wevers RA, Superti-Furga A. van Karnebeek CDM, et al. Nat Genet. 2017 May 26;49(6):969. doi: 10.1038/ng0617-969a. Nat Genet. 2017. PMID: 28546570 No abstract available.

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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References

1. Development. 2008 May;135(10):1735-43 - PubMed
1. ACS Chem Biol. 2015 Oct 16;10(10):2353-63 - PubMed
1. Nature. 2014 Jul 17;511(7509):344-7 - PubMed
1. Glycobiology. 2012 Sep;22(9):1147-62 - PubMed
1. Mol Cell Biol. 2001 Aug;21(16):5512-9 - PubMed

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[1] Development. 2008 May;135(10):1735-43 - PubMed

[2] Development. 2008 May;135(10):1735-43 - PubMed

[3] ACS Chem Biol. 2015 Oct 16;10(10):2353-63 - PubMed

[4] ACS Chem Biol. 2015 Oct 16;10(10):2353-63 - PubMed

[5] Nature. 2014 Jul 17;511(7509):344-7 - PubMed

[6] Nature. 2014 Jul 17;511(7509):344-7 - PubMed

[7] Glycobiology. 2012 Sep;22(9):1147-62 - PubMed

[8] Glycobiology. 2012 Sep;22(9):1147-62 - PubMed

[9] Mol Cell Biol. 2001 Aug;21(16):5512-9 - PubMed

[10] Mol Cell Biol. 2001 Aug;21(16):5512-9 - PubMed

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

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

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