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

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.

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.

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.

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.