Catalytic deficiency of O-GlcNAc transferase leads to X-linked intellectual disability

Veronica Pravata, Villo Muha, Mehmet Gundogdu, Andrew Ferenbach, Poonam Kakade, Vasudha Vandadi, Ariane C. Wilmes, Vladimir Borodkin, Shelagh Joss, Marios Stavridis, Daan van Aalten (Lead / Corresponding author)

Research output: Contribution to journalArticle

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Abstract

O-GlcNAc transferase (OGT) is an X-linked gene product that is essential for normal development of the vertebrate embryo. It catalyses the O-GlcNAc posttranslational modification of nucleocytoplasmic proteins and proteolytic maturation of the transcriptional coregulator Host cell factor 1 (HCF1). Recent studies have suggested that conservative missense mutations distal to the OGT catalytic domain lead to X-linked intellectual disability in boys, but it is not clear if this is through changes in the O-GlcNAc proteome, loss of protein–protein interactions, or misprocessing of HCF1. Here, we report an OGT catalytic domain missense mutation in monozygotic female twins (c. X:70779215 T > A, p. N567K) with intellectual disability that allows dissection of these effects. The patients show limited IQ with developmental delay and skewed X-inactivation. Molecular analyses revealed decreased OGT stability and disruption of the substrate binding site, resulting in loss of catalytic activity. Editing this mutation into the Drosophila genome results in global changes in the O-GlcNAc proteome, while in mouse embryonic stem cells it leads to loss of O-GlcNAcase and delayed differentiation down the neuronal lineage. These data imply that catalytic deficiency of OGT could contribute to X-linked intellectual disability.

Original languageEnglish
Pages (from-to)14961-14970
Number of pages10
JournalProceedings of the National Academy of Sciences
Volume116
Issue number30
Early online date11 Jul 2019
DOIs
Publication statusPublished - 23 Jul 2019

Fingerprint

Intellectual Disability
Host Factor 1 Protein
Missense Mutation
Proteome
Catalytic Domain
X Chromosome Inactivation
X-Linked Genes
Monozygotic Twins
Post Translational Protein Processing
Drosophila
Embryonic Development
Vertebrates
Dissection
Binding Sites
O-GlcNAc transferase
Genome
Mutation
Proteins

Keywords

  • intellectual disability
  • O-GlcNAc
  • neurodevelopment
  • Intellectual disability
  • Neurodevelopment

Cite this

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title = "Catalytic deficiency of O-GlcNAc transferase leads to X-linked intellectual disability",
abstract = "O-GlcNAc transferase (OGT) is an X-linked gene product that is essential for normal development of the vertebrate embryo. It catalyses the O-GlcNAc posttranslational modification of nucleocytoplasmic proteins and proteolytic maturation of the transcriptional coregulator Host cell factor 1 (HCF1). Recent studies have suggested that conservative missense mutations distal to the OGT catalytic domain lead to X-linked intellectual disability in boys, but it is not clear if this is through changes in the O-GlcNAc proteome, loss of protein–protein interactions, or misprocessing of HCF1. Here, we report an OGT catalytic domain missense mutation in monozygotic female twins (c. X:70779215 T > A, p. N567K) with intellectual disability that allows dissection of these effects. The patients show limited IQ with developmental delay and skewed X-inactivation. Molecular analyses revealed decreased OGT stability and disruption of the substrate binding site, resulting in loss of catalytic activity. Editing this mutation into the Drosophila genome results in global changes in the O-GlcNAc proteome, while in mouse embryonic stem cells it leads to loss of O-GlcNAcase and delayed differentiation down the neuronal lineage. These data imply that catalytic deficiency of OGT could contribute to X-linked intellectual disability.",
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author = "Veronica Pravata and Villo Muha and Mehmet Gundogdu and Andrew Ferenbach and Poonam Kakade and Vasudha Vandadi and Wilmes, {Ariane C.} and Vladimir Borodkin and Shelagh Joss and Marios Stavridis and {van Aalten}, Daan",
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Catalytic deficiency of O-GlcNAc transferase leads to X-linked intellectual disability. / Pravata, Veronica; Muha, Villo; Gundogdu, Mehmet; Ferenbach, Andrew; Kakade, Poonam; Vandadi, Vasudha ; Wilmes, Ariane C. ; Borodkin, Vladimir; Joss, Shelagh; Stavridis, Marios; van Aalten, Daan (Lead / Corresponding author).

In: Proceedings of the National Academy of Sciences, Vol. 116, No. 30, 23.07.2019, p. 14961-14970.

Research output: Contribution to journalArticle

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AU - Pravata, Veronica

AU - Muha, Villo

AU - Gundogdu, Mehmet

AU - Ferenbach, Andrew

AU - Kakade, Poonam

AU - Vandadi, Vasudha

AU - Wilmes, Ariane C.

AU - Borodkin, Vladimir

AU - Joss, Shelagh

AU - Stavridis, Marios

AU - van Aalten, Daan

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PY - 2019/7/23

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