Epileptogenic mosaic brain malformations: a single-cell and spatial transcriptomic landscape

Baldassari, Sara; Gomez Teijeiro, Lucia; Klingler, Esther; Sami, Lina; Bizzotto, Sara; Doladilhe, Marion; Ferrand-Sorbets, Sarah; Dorfmuller, George; Chipaux, Mathilde; Adle-Biassette, Homa; Jabaudon, Denis; Baulac, Stéphanie (2024). Epileptogenic mosaic brain malformations: a single-cell and spatial transcriptomic landscape European Journal of Human Genetics, 32, p. 62. Cham: Springer Nature https://doi.org/10.1038/s41431-023-01480-z

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Brain somatic mutations in mTOR pathway genes are the primary etiology of focal cortical dysplasia type II (FCDII), a brain malformation characterized by cortical dyslamination and the presence of mTOR-hyperactive dysmorphic neurons and balloon cells. FCDII is a significant cause of drug-resistant epilepsy in children who undergo epilepsy surgery to control seizures. The neurodevelopmental effects of mTOR pathway somatic mutations and the affected cell types remain unclear. We investigated ten surgical FCDII tissues with somatic mTOR-activating mutations using histological, genetic, single-cell, and spatial transcriptomic approaches. Histopathology measures revealed that dysmorphic neurons and balloon cells, although enriched for the mutations, only represent a minor fraction (<10%) of mutated cells in the dysplastic tissues. Transcriptomic analysis of laser-captured pools of dysmorphic neurons showed their immature principal neurons signature, while balloon cells correlated with the astrocytic cell lineage and displayed transcriptomic signatures usually observed in neuroglial progenitor cells. By combining single-nuclei profiling and long-read sequencing, we showed that FCDII somatic mutations affect multiple brain cell lineages, thus suggesting they occurred at early developmental stages. Moreover, we observed that mTOR-activating mutations in different cell types lead to cell-specific transcriptomic alterations. Finally, using spatial transcriptomics, we correlated histological and gene expression alterations, thus allowing unprecedented insights into FCDII pathology. Our results highlight an unforeseen diversity of FCDII cell types affected by mTOR pathway mutations and represent a significant resource for better understanding FCDII-related epilepsy and identifying biomarkers for targeted therapeutics.

Item Type:	Conference or Workshop Item (Abstract)
Division/Institute:	Business School > Institute for Applied Data Science & Finance Business School > Institute for Applied Data Science & Finance > Applied Data Science Business School
Name:	Baldassari, Sara; Gomez Teijeiro, Lucia; Klingler, Esther; Sami, Lina; Bizzotto, Sara; Doladilhe, Marion; Ferrand-Sorbets, Sarah; Dorfmuller, George; Chipaux, Mathilde; Adle-Biassette, Homa; Jabaudon, Denis and Baulac, Stéphanie
Subjects:	Q Science > Q Science (General) R Medicine > R Medicine (General) R Medicine > RB Pathology
ISSN:	1018-4813
Publisher:	Springer Nature
Language:	Español
Submitter:	Lucia Gomez Teijeiro
Date Deposited:	11 Sep 2024 09:33
Last Modified:	11 Sep 2024 09:33
Publisher DOI:	https://doi.org/10.1038/s41431-023-01480-z
PubMed ID:	PMC10772079
ARBOR DOI:	10.24451/arbor.22399
URI:	https://arbor.bfh.ch/id/eprint/22399