Disrupted O-GalNAc glycosylation as a mechanism and biomarker of <i>SLC35A2</i> -associated epilepsy
Rare germline and somatic variants in <i>SLC35A2</i> cause a spectrum of severe glycosylation disorders that commonly present with epilepsy. <i>SLC35A2</i> encodes the Golgi transporter for UDP-galactose, but how its deficiency leads to severe neurodevelopmental disorders is unknown. Using a mouse model deficient for <i>Slc35a2</i> in the forebrain, we identified a specific defect in O-GalNAc glycan synthesis, while other galactose-containing glycoconjugates remained intact. O-GalNAc glycans were absent from their normal location within neuronal tracts of the corpus callosum, and truncated precursors accumulated in the cortex on critical extracellular matrix molecules. Cultured primary neurons lacking <i>Slc35a2</i> showed impaired development, hyperexcitability, and impaired O-GalNAc glycosylation. Finally, human brain tissue from cases of <i>SLC35A2</i> -associated intractable epilepsy displayed a strong correlation between variant burden and truncated O-GalNAc glycans. These findings provide a mechanistic link between genetic causes of <i>SLC35A2</i> -associated epilepsy and protein O-glycosylation that can be targeted for biomarker and therapeutic development.
Authors
- Savannah Muron
- Brianna M. Masters (ORCID: https://orcid.org/0009-0006-6258-3565)
- Daniel C. Koboldt (ORCID: https://orcid.org/0000-0002-7290-3482)
- Richard D. Cummings (ORCID: https://orcid.org/0000-0002-8918-5034)
- Julia Furnari
- Maxence Noël (ORCID: https://orcid.org/0000-0003-2621-7374)
- Samuel H. Barth (ORCID: https://orcid.org/0000-0003-4823-3076)
- Robert G. Mealer (ORCID: https://orcid.org/0000-0001-5963-2836)
- Amanda Ringland
- Adam P. Ostendorf (ORCID: https://orcid.org/0000-0002-9994-6650)
- Christopher R. Pierson (ORCID: https://orcid.org/0000-0002-5553-3096)
- Erin L Heinzen
- James J. Anderson (ORCID: https://orcid.org/0009-0004-7326-5787)
- Edward Yang
- Alissa M DGama
- Kaitlyn DJ Huizar
- Annapurna Poduri Poduri
- Tracy A Bedrosian
- Sheridan L Smith
- MaryAnn E Bowyer
- Hart GW Lidov
- Diana L Thomas
- Hyojung Yoon
- Sahibjot Sran
- Peter D Canoll
- Benjamin D Philpot
Institutions
- Broad Institute (US)
- University of North Carolina at Chapel Hill (US)
- Boston Children's Hospital (US)
- Nationwide Children's Hospital (US)
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- Columbia University Irving Medical Center (US)
- Neurological Surgery (US)
- The Ohio State University (US)
- Columbia University (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-03-04
- DOI
- https://doi.org/10.64898/2026.03.02.708854
- Primary Topic
- Glycosylation and Glycoproteins Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00