Human brain tissue with MOGHE carrying somatic SLC35A2 variants reveal aberrant protein expression and protein loss in the white matter

• DOI: 10.1007/s00401-025-02858-7
• Publication Date: 2025-03-05T06:25:16Z
• Authors: Erica Cecchini; Simon Geffers; Roland Coras; Dorothea Schultheis; Christian Holtzha...; Kristina Karandas...; Harald Herrmann; Friedrich Paulsen; Christine Stadelmann; Katja Kobow; Till Hartlieb; Christian G. Bien; Dennis Lal; Ingmar Blumcke; Lucas Hoffmann
• Keywords: Brain tissue; Human brain; White (mutation)

Mild Malformation of Cortical Development with Oligodendroglial Hyperplasia in Epilepsy (MOGHE) is a recently described disease entity primarily affecting young children drug-resistant epilepsy, mainly the frontal lobe. The condition histopathologically defined by focal lesions patchy areas increased oligodendroglial cell density at grey-white matter boundary and heterotopic neurons white matter. Approximately half individuals MOGHE carry brain somatic variants SLC35A2 gene, which affects UDP-galactose transporter thus sphingolipid glycosylation. To investigate impact on protein expression, we analysed tissue without mosaicism, distinguishing missense from nonsense variants. We developed an antibody targeting N-terminus galactose applied it for immunofluorescence (IF) analyses cohort comprising 59 genetically tested selected three centres Germany. included 13 15 Our findings confirm localisation Golgi apparatus all neuroepithelial types as well within outposts along processes. distribution was altered samples dependent variant its allelic frequency. Western blot IF revealed significant reduction tissues carrying Ultrastructural demonstrated hypomyelination regions densities, regardless harbouring Notably, this pattern decreased age. These results suggested role pathogenesis indicated presence additional myelin-associated pathomechanisms those who do not pathogenic variant.