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 language | English |
|---|---|
| Pages (from-to) | 14961-14970 |
| Number of pages | 10 |
| Journal | Proceedings of the National Academy of Sciences |
| Volume | 116 |
| Issue number | 30 |
| Early online date | 11 Jul 2019 |
| DOIs | |
| Publication status | Published - 23 Jul 2019 |
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Keywords
- intellectual disability
- O-GlcNAc
- neurodevelopment
- Intellectual disability
- Neurodevelopment
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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 journal › Article
TY - JOUR
T1 - Catalytic deficiency of O-GlcNAc transferase leads to X-linked intellectual disability
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
N1 - Copyright © 2019 the Author(s). Published by PNAS.
PY - 2019/7/23
Y1 - 2019/7/23
N2 - 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.
AB - 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.
KW - intellectual disability
KW - O-GlcNAc
KW - neurodevelopment
KW - Intellectual disability
KW - Neurodevelopment
UR - http://www.scopus.com/inward/record.url?scp=85069732104&partnerID=8YFLogxK
U2 - 10.1073/pnas.1900065116
DO - 10.1073/pnas.1900065116
M3 - Article
VL - 116
SP - 14961
EP - 14970
JO - Proceedings of the National Academy of Sciences
JF - Proceedings of the National Academy of Sciences
SN - 0027-8424
IS - 30
ER -