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

C. Van Karnebeek, Luisa Bonafé, Xiao Yan Wen, Maja Tarailo-Graovac, Sara Balzano, Beryl Royer-Bertrand, Angel Ashikov, Livia Garavelli, Isabella Mammi, Licia Turolla, Catherine Breen, Dian Donnai, Valerie Cormier, Délphine Heron, Gen Nishimura, Shinichi Uchikawa, Belinda Campos-Xavier, Antonio Rossi, T. Hennet, Koroboshka Brand-Arzamendi & 26 others Jacob Rozmus, Keith Harshman, Brian Stevenson, Enrico Girardi, Giulio Superti-Furga, Tammie Dewan, Alissa Collingridge, Jessie Halparin, Colin J. Ross, Margot Van Allen, Andrea Rossi, Udo Engelke, Leo A J Kluijtmans, Ed Van Der Heeft, Herma Renkema, Arjan P. De Brouwer, Karin Huijben, Fokje Zijlstra, Thorben Heisse, Thomas Boltje, Wyeth W. Wasserman, Carlo Rivolta, Sheila Unger, Dirk J. Lefeber, Ron A. Wevers, Andrea Superti-Furga

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)777-784
Number of pages8
JournalNature Genetics
Volume48
Issue number7
DOIs
Publication statusPublished - Jul 1 2016

Fingerprint

N-Acetylneuraminic Acid
Brain
Body Fluids
Zebrafish
Growth and Development
Blood Proteins
Glycoproteins
Embryonic Structures
Fibroblasts
Phenotype
Mutation
Genes

ASJC Scopus subject areas

  • Medicine(all)
  • Genetics

Cite this

Van Karnebeek, C., Bonafé, L., Wen, X. Y., Tarailo-Graovac, M., Balzano, S., Royer-Bertrand, B., ... Superti-Furga, A. (2016). NANS-mediated synthesis of sialic acid is required for brain and skeletal development. Nature Genetics, 48(7), 777-784. https://doi.org/10.1038/ng.3578

NANS-mediated synthesis of sialic acid is required for brain and skeletal development. / Van Karnebeek, C.; Bonafé, Luisa; Wen, Xiao Yan; Tarailo-Graovac, Maja; Balzano, Sara; Royer-Bertrand, Beryl; Ashikov, Angel; Garavelli, Livia; Mammi, Isabella; Turolla, Licia; Breen, Catherine; Donnai, Dian; Cormier, Valerie; Heron, Délphine; Nishimura, Gen; Uchikawa, Shinichi; Campos-Xavier, Belinda; Rossi, Antonio; Hennet, T.; Brand-Arzamendi, Koroboshka; Rozmus, Jacob; Harshman, Keith; Stevenson, Brian; Girardi, Enrico; Superti-Furga, Giulio; Dewan, Tammie; Collingridge, Alissa; Halparin, Jessie; Ross, Colin J.; Van Allen, Margot; Rossi, Andrea; Engelke, Udo; Kluijtmans, Leo A J; Van Der Heeft, Ed; Renkema, Herma; De Brouwer, Arjan P.; Huijben, Karin; Zijlstra, Fokje; Heisse, Thorben; Boltje, Thomas; Wasserman, Wyeth W.; Rivolta, Carlo; Unger, Sheila; Lefeber, Dirk J.; Wevers, Ron A.; Superti-Furga, Andrea.

In: Nature Genetics, Vol. 48, No. 7, 01.07.2016, p. 777-784.

Research output: Contribution to journalArticle

Van Karnebeek, C, 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, B, Girardi, E, Superti-Furga, G, Dewan, T, Collingridge, A, Halparin, J, Ross, CJ, Van Allen, M, Rossi, A, Engelke, U, Kluijtmans, LAJ, Van Der Heeft, E, Renkema, H, De Brouwer, AP, Huijben, K, Zijlstra, F, Heisse, T, Boltje, T, Wasserman, WW, Rivolta, C, Unger, S, Lefeber, DJ, Wevers, RA & Superti-Furga, A 2016, 'NANS-mediated synthesis of sialic acid is required for brain and skeletal development', Nature Genetics, vol. 48, no. 7, pp. 777-784. https://doi.org/10.1038/ng.3578
Van Karnebeek C, Bonafé L, Wen XY, Tarailo-Graovac M, Balzano S, Royer-Bertrand B et al. NANS-mediated synthesis of sialic acid is required for brain and skeletal development. Nature Genetics. 2016 Jul 1;48(7):777-784. https://doi.org/10.1038/ng.3578
Van Karnebeek, C. ; Bonafé, Luisa ; Wen, Xiao Yan ; Tarailo-Graovac, Maja ; Balzano, Sara ; Royer-Bertrand, Beryl ; Ashikov, Angel ; Garavelli, Livia ; Mammi, Isabella ; Turolla, Licia ; Breen, Catherine ; Donnai, Dian ; Cormier, Valerie ; Heron, Délphine ; Nishimura, Gen ; Uchikawa, Shinichi ; Campos-Xavier, Belinda ; Rossi, Antonio ; Hennet, T. ; Brand-Arzamendi, Koroboshka ; Rozmus, Jacob ; Harshman, Keith ; Stevenson, Brian ; Girardi, Enrico ; Superti-Furga, Giulio ; Dewan, Tammie ; Collingridge, Alissa ; Halparin, Jessie ; Ross, Colin J. ; Van Allen, Margot ; Rossi, Andrea ; Engelke, Udo ; Kluijtmans, Leo A J ; Van Der Heeft, Ed ; Renkema, Herma ; De Brouwer, Arjan P. ; Huijben, Karin ; Zijlstra, Fokje ; Heisse, Thorben ; Boltje, Thomas ; Wasserman, Wyeth W. ; Rivolta, Carlo ; Unger, Sheila ; Lefeber, Dirk J. ; Wevers, Ron A. ; Superti-Furga, Andrea. / NANS-mediated synthesis of sialic acid is required for brain and skeletal development. In: Nature Genetics. 2016 ; Vol. 48, No. 7. pp. 777-784.
@article{db0328fffea44684830e001e0c2a6e00,
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.",
author = "{Van Karnebeek}, C. and Luisa Bonaf{\'e} and Wen, {Xiao Yan} and Maja Tarailo-Graovac and Sara Balzano and Beryl Royer-Bertrand and Angel Ashikov and Livia Garavelli and Isabella Mammi and Licia Turolla and Catherine Breen and Dian Donnai and Valerie Cormier and D{\'e}lphine Heron and Gen Nishimura and Shinichi Uchikawa and Belinda Campos-Xavier and Antonio Rossi and T. Hennet and Koroboshka Brand-Arzamendi and Jacob Rozmus and Keith Harshman and Brian Stevenson and Enrico Girardi and Giulio Superti-Furga and Tammie Dewan and Alissa Collingridge and Jessie Halparin and Ross, {Colin J.} and {Van Allen}, Margot and Andrea Rossi and Udo Engelke and Kluijtmans, {Leo A J} and {Van Der Heeft}, Ed and Herma Renkema and {De Brouwer}, {Arjan P.} and Karin Huijben and Fokje Zijlstra and Thorben Heisse and Thomas Boltje and Wasserman, {Wyeth W.} and Carlo Rivolta and Sheila Unger and Lefeber, {Dirk J.} and Wevers, {Ron A.} and Andrea Superti-Furga",
year = "2016",
month = "7",
day = "1",
doi = "10.1038/ng.3578",
language = "English",
volume = "48",
pages = "777--784",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "7",

}

TY - JOUR

T1 - NANS-mediated synthesis of sialic acid is required for brain and skeletal development

AU - Van Karnebeek, C.

AU - Bonafé, Luisa

AU - Wen, Xiao Yan

AU - Tarailo-Graovac, Maja

AU - Balzano, Sara

AU - Royer-Bertrand, Beryl

AU - Ashikov, Angel

AU - Garavelli, Livia

AU - Mammi, Isabella

AU - Turolla, Licia

AU - Breen, Catherine

AU - Donnai, Dian

AU - Cormier, Valerie

AU - Heron, Délphine

AU - Nishimura, Gen

AU - Uchikawa, Shinichi

AU - Campos-Xavier, Belinda

AU - Rossi, Antonio

AU - Hennet, T.

AU - Brand-Arzamendi, Koroboshka

AU - Rozmus, Jacob

AU - Harshman, Keith

AU - Stevenson, Brian

AU - Girardi, Enrico

AU - Superti-Furga, Giulio

AU - Dewan, Tammie

AU - Collingridge, Alissa

AU - Halparin, Jessie

AU - Ross, Colin J.

AU - Van Allen, Margot

AU - Rossi, Andrea

AU - Engelke, Udo

AU - Kluijtmans, Leo A J

AU - Van Der Heeft, Ed

AU - Renkema, Herma

AU - De Brouwer, Arjan P.

AU - Huijben, Karin

AU - Zijlstra, Fokje

AU - Heisse, Thorben

AU - Boltje, Thomas

AU - Wasserman, Wyeth W.

AU - Rivolta, Carlo

AU - Unger, Sheila

AU - Lefeber, Dirk J.

AU - Wevers, Ron A.

AU - Superti-Furga, Andrea

PY - 2016/7/1

Y1 - 2016/7/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84969834515&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84969834515&partnerID=8YFLogxK

U2 - 10.1038/ng.3578

DO - 10.1038/ng.3578

M3 - Article

VL - 48

SP - 777

EP - 784

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 7

ER -