Identyfikacja kluczowych genów związanych z komórkami mikroglii i dwugenowy model diagnostyczny CX3CR1/P2RY12 dla różnych typów rozmaitości korowych towarzyszących epilepsji: zintegrowana analiza danych genetycznych z zewnętrzną walidacją
PubMed➕ 25.10.2026Front Neurosci
Identification of microglia-associated hub genes and a CX3CR1/P2RY12 two-gene diagnostic model for cross-subtype epilepsy-associated cortical malformations: integrated transcriptomic analysis with external validation
W skrócie
Naukowcy przeanalizowali dane genetyczne z mózgów pacjentów z epilepsją oporną na leki i znaleźli, że różne typy zmian strukturalnych w mózgu (dysplazja ogniskowa i stwardnienie guzowate) mają wspólny mechanizm - wzmożoną aktywność komórek immunologicznych zwanych mikroglią. Badacze opracowali prosty test diagnostyczny oparty na dwóch genach (CX3CR1 i P2RY12), który może pomóc w rozpoznawaniu tych schorzeń z dokładnością ponad 85 procent. Odkrycia te sugerują potencjalnie nowe możliwości leczenia poprzez wpływ na aktywność tych komórek immunologicznych.
Oryginalny abstract (angielski)
Focal cortical dysplasia (FCD) and tuberous sclerosis complex (TSC) are major causes of drug-resistant epilepsy, yet shared molecular mechanisms across these structurally distinct malformations remain poorly characterized. We performed an integrated transcriptomic analysis of RNA-seq data from GSE256068 [85 samples: 64 cortical (FCD2a, FCD2b, TSC, controls) and 21 hippocampal (TLE-HS, controls)]. Differential expression analysis with limma identified 865, 1,915, 2,772, and 3,749 DEGs in FCD2a, FCD2b, TSC, and TLE-HS versus controls, respectively, with 49 shared DEGs across all four subtypes. Weighted gene co-expression network analysis (WGCNA) identified the brown and red modules as key disease-associated modules. By intersecting WGCNA hub genes (|GS| > 0.5, |MM| > 0.8) with shared DEGs, we identified 15 hub genes, all functionally associated with microglia/myeloid lineage, including IRF8, TLR7, CX3CR1, P2RY12, C3AR1, and CCR1. Gene set enrichment analysis (GSEA) revealed 15 KEGG pathways consistently enriched across all subtypes, converging on Toll-like receptor, NF-kB, chemokine, and complement signaling. Immune deconvolution using MCP-counter and xCell confirmed elevated monocytic lineage and T cell infiltration in disease cortex, with monocytic scores showing a positive trend with seizure frequency. A two-gene logistic regression model (CX3CR1 + P2RY12), selected by LASSO and random forest, achieved a training AUC of 0.979 and a nested five-fold cross-validation AUC of 0.862 (95% CI: 0.693-1.000), with an external validation AUC of 0.865 (95% CI: 0.681-1.000) in GSE213488. Drug repurposing via Enrichr identified vorinostat (HDAC inhibitor) as a top candidate, and IRF8 was predicted as the master transcriptional regulator. , mTOR activation with MHY1485 preserved P2ry12 expression in BV-2 microglia, whereas LPS stimulation induced its loss, supporting a distinct microglia/myeloid-associated program driven by mTOR hyperactivity. These findings demonstrate that cross-subtype transcriptomic convergence on microglial innate immune activation represents a unifying molecular mechanism in FCD and TSC, and that CX3CR1 and P2RY12 together constitute a two-gene diagnostic classifier with encouraging but preliminary performance with potential clinical utility.