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Nat Genet. 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.

Author information

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.

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.

PMID:
27213289
DOI:
10.1038/ng.3578
[Indexed for MEDLINE]
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