Single-cell genotyping and transcriptomic profiling of mosaic focal cortical dysplasia
Focal cortical dysplasia type II (FCDII) is a cortical malformation causing refractory epilepsy. FCDII arises from developmental somatic activating mutations in mTOR pathway genes, leading to focal cortical dyslamination and abnormal cytomegalic cells. Which cell types carry pathogenic mutations and how they affect cell-type-specific transcriptional programs remain unknown. In the present study, we combined several single-nucleus genotyping and transcriptomics approaches with spatial resolution in surgical cortical specimens from patients with genetically mosaic FCDII. Mutations were detected in distinct cell types, including glutamatergic neurons and astrocytes, and a small fraction of mutated cells exhibited cytomegalic features. Moreover, we identified cell-type-specific transcriptional dysregulations in both mutated and nonmutated FCDII cells, including synapse- and neurodevelopment-related pathways, that may account for epilepsy and dysregulation of mitochondrial metabolism pathways in cytomegalic cells. Together, these findings reveal cell-autonomous and non-cell-autonomous features of FCDII that may be leveraged for precision medicine.
Authors
- Eleonora Aronica (ORCID: https://orcid.org/0000-0002-3542-3770)
- Homa Adle‐Biassette (ORCID: https://orcid.org/0000-0001-9446-8306)
- Sergi Roig‐Puiggros (ORCID: https://orcid.org/0000-0001-5909-218X)
- Lucia Gomez Teijeiro
- Théo Ribierre (ORCID: https://orcid.org/0000-0002-5003-0991)
- Sara Bizzotto (ORCID: https://orcid.org/0000-0001-6644-0306)
- Sara Baldassari (ORCID: https://orcid.org/0000-0003-4851-2796)
- Mathilde Chipaux (ORCID: https://orcid.org/0000-0002-8454-7374)
- Denis Jabaudon (ORCID: https://orcid.org/0000-0003-2438-4769)
- Marion Doladilhe (ORCID: https://orcid.org/0009-0000-7502-9850)
- Stéphanie Baulac (ORCID: https://orcid.org/0000-0001-6430-4693)
- Esther Klingler (ORCID: https://orcid.org/0000-0002-6577-1362)
- Corentin Raoux
- Lina Sami (ORCID: https://orcid.org/0009-0002-8422-8186)
- Alice Gilbert (ORCID: https://orcid.org/0000-0003-0102-1826)
- J. Couturier
Institutions
- University of Geneva (CH)
- Centre National de la Recherche Scientifique (FR)
- Allen Institute for Brain Science (US)
- Inserm (FR)
- Université Paris Cité (FR)
- Sorbonne Université (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- University Hospital of Geneva (CH)
- Amsterdam Neuroscience (NL)
- Hôpital Lariboisière (FR)
- Fondation de Rothschild (FR)
- Amsterdam University Medical Centers (NL)
- Institut du Cerveau (FR)
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- NeuroDiderot (FR)
- University of Amsterdam (NL)
Publication Details
- Journal
- Nature Neuroscience
- Published
- 2025-04-30
- DOI
- https://doi.org/10.1038/s41593-025-01936-z
- Citations
- 27
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 21.76