Mosaic human cortical organoids model mTOR-related focal cortical dysplasia through DEPDC5 deletion - PubMed
5 days ago
- #mTOR signaling
- #epilepsy
- #neurodevelopmental disorders
- Mosaic human cortical organoids (hCOs) model mTOR-related focal cortical dysplasia (FCDII) through DEPDC5 deletion.
- FCDII is a major cause of pediatric drug-resistant epilepsy, linked to mTOR pathway gene mutations, including DEPDC5 loss-of-function variants.
- Mosaic hCOs showed increased mTOR activity, rescued by rapamycin, and exhibited dysmorphic neurons and enhanced excitability, mimicking FCDII pathology.
- Single-cell transcriptomics revealed aberrant neuron differentiation, premature upper-layer neuron generation, and altered synaptic/epilepsy-related gene expression.
- DEPDC5 deficiency disrupts human corticogenesis, with mosaic biallelic inactivation being necessary for FCDII pathogenesis.