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Exploiting O-GlcNAc dyshomeostasis to screen O-GlcNAc transferase intellectual disability variants
Huijie Yuan1, Conor W Mitchell2, Andrew T Ferenbach3
1Section for Neurobiology, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark; Danish Research Institute of Translational Neuroscience DANDRITE-Nordic EMBL Partnership for Molecular Medicine, Aarhus University, Aarhus, Denmark; Division of Molecular, Cell and Developmental Biology, School of Life Sciences, University of Dundee, Dundee, UK.
Researchers developed a new method to identify disease-causing O-GlcNAc transferase (OGT) variants in OGT congenital disorder of glycosylation (OGT-CDG). This approach helps predict variant pathogenicity and reveals reduced O-GlcNAc homeostasis disruption as a common OGT-CDG mechanism.
Area of Science:
- Biochemistry
- Genetics
- Cell Biology
Background:
- O-GlcNAcylation is a critical post-translational modification catalyzed by O-GlcNAc transferase (OGT).
- Missense variants in OGT cause OGT congenital disorder of glycosylation (OGT-CDG), a rare intellectual disability syndrome.
- The pathogenic mechanisms of OGT variants and methods to distinguish them remain unclear.
Purpose of the Study:
- To develop a method for assessing the pathogenicity of OGT variants.
- To investigate the impact of OGT variants on O-GlcNAc homeostasis.
- To enable accurate prediction of de novo OGT-CDG variants.
Main Methods:
- Developed a double-fluorescence assay in mouse embryonic stem cells.
- Quantified the effects of OGT variants on endogenous OGT expression to assess O-GlcNAc homeostasis disruption.
- Validated the assay by distinguishing OGT-CDG variants from wild-type and population variants.
Main Results:
- OGT-CDG variants showed a reduced feedback response compared to wild-type and gnomAD variants.
- The assay successfully differentiated pathogenic OGT-CDG variants from background variants.
- Reduced disruption of O-GlcNAc homeostasis was identified as a common mechanism in OGT-CDG.
Conclusions:
- The developed double-fluorescence strategy effectively predicts OGT variant pathogenicity.
- This method aids in diagnosing and understanding OGT-CDG.
- Reduced O-GlcNAc homeostasis disruption is a key pathogenic mechanism in OGT-CDG.
