Investigation of Unknown Neurogenetic Variants: Integrative Computational Analysis Reveals Critical Variants of GABRB3 Gene Associated with Epilepsy

Authors : Derya Türkmen Delioğlu, Ayla Arslan

Pages : 1239-1260

Doi:10.35414/akufemubid.1622931

View : 363 | Download : 459

Publication Date : 2025-12-03

Article Type : Research Paper

Abstract :Alterations of GABA (A) receptors are linked to various disorders including epilepsy, which is diagnosed through a comprehensive approach including genetic screening. The functional consequence of many genetic variants in the β3 subunit of the GABA(A) receptor remain unknown. This presents a challenge for genetic testing and precision medicine. Addressing this obstacle, in the present study, we analyzed the 141 missense variants with unknown function in the GABRB3 gene using a comprehensive in silico approach. Algorithmic computing based on the sequence homology and other features including the functional and disease-related analysis of missense variants revealed the prediction of the most pathogenic variants, mapped onto the different domains of the β3 subunit, with Y48C, D49E, D73H, M80R, D94E, H132Y, R142C, P169L, C175W and Y182H being located in the N terminus extracellular domain, S264F in the first transmembrane domain, G279R, T281A the second transmembrane region, R294Q is at the end of the second transmembrane domain, P298S in the linker between the second and the third transmembrane domains, and Y467S/H in the fourth transmembrane domains. These variants were generally associated with childhood absence epilepsy. Our results provide guidance for the laboratory research aiming for the identification of new pathogenic epilepsy mutations.
Keywords : Epilepsi, GABA (A) reseptörü, Belirsiz Anlamlı Varyant (VUS)

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