Exploring GABA - A Receptor Subunit Mutations and Their Role in Epilepsy Pathophysiology

A BSTRACT Background: Epilepsy, marked by recurrent seizures, often arises from impaired inhibitory neurotransmission. Gamma-aminobutyric acid type A (GABA_A) receptors, particularly the α1 subunit encoded by GABRA1, are central to neuronal excitability. Although GABRA1 variants are linked to epilepsy, their molecular impact remains unclear. Objectives: To evaluate the structural and functional consequences of GABRA1 variants using computational approaches and clarify their role in epilepsy pathophysiology. Materials and Methods: A total of 137 GABRA1 missense variants were retrieved from ClinVar. Pathogenicity was assessed using ClinPred, REVEL, and FATHMM-XF. Conservation analysis was performed with ConSurf, and structural modeling with the HOPE server and UCSF Chimera. Functional domain mapping utilized UniProt and NCBI databases. Results: Eight variants (L49H, P59L, W97R, D99G, G152S, V270G, T294R, P305L) were consistently predicted to be deleterious. These mutations, mostly at conserved residues, localized to extracellular, ligand-binding, and transmembrane domains. Structural modeling revealed disruptions in receptor folding, ligand binding, and ion channel gating, indicating impaired GABAergic signaling and possible links to drug resistance. Conclusion: In silico analysis highlights critical GABRA1 variants that may drive epileptogenesis by altering receptor structure and function. These findings support integrating computational genomics into precision medicine strategies for epilepsy management.