Hassas Tıp için Bütünleşik Biyoinformatik Yaklaşım: İnsan GABRG2 Geninin Hücre Patolojisi ve Epilepsi Fenotip Şiddeti ile Karakterize Patojenik Varyantlarının Tahmini

Abstract

GABRG2 genindeki belirsiz anlam varyantların yorumlanması, epilepsi hassas tıpı için kritik önem teşkil etmektedir. Çalışmamız, ClinVar veri tabanındaki 156 GABRG2 belirsiz anlam varyantına odaklanarak, γ2 alt biriminde 10 patojenik varyantı belirledi. Hasta mutasyonları ve mutagenez çalışmalarıyla entegrasyon sonucunda varyantların epileptojenik yapısal kasetler içinde konumlandırılmasıyla, fenotip şiddeti ve hücresel patoloji karakterize edildi. 3 tane N-terminus ekstrasellüler bölge varyantı daha az şiddetli ve 7 tane transmembran bölge varyantı daha şiddetli epilepsi fenotipleri ile eksilmiş hücre yüzeyi ifadesi ve akımla bağlantılı olarak öngörüldü. Özellikle, 4 transmembran bölge varyantının kanal iletkenliğini bozabileceği belirlendi. Araştırmamız, ACMG/AMP kriterleri PP3 ve PM1 ile uyumludur.

Keywords

• Epilepsi
• In siliko
• Patojenik varyant
• GABA (A) reseptörü
• Hassas Tıp
• Gama-2 alt birimi

Integrated Bioinformatic Approach for Precision Medicine: Prediction of Human GABRG2 Gene Pathogenic Variants, Characterized with Cellular Pathology and Epilepsy Phenotype Severity

Abstract

Interpreting GABRG2 variants of unknown significance hinders epilepsy precision medicine. Using computer algorithms, our study focused on 156 GABRG2 variants from ClinVar, identifying 10 highly pathogenic variants within the γ2 subunit. Integration with patient mutations and mutagenesis studies locates variants within epileptogenic structural cassettes, aiding phenotype severity and cellular pathology characterization. Our results predict milder phenotypes for 3 N-terminus extracellular domain variants and more severe phenotypes for 7 transmembrane domain variants, linked to cellular pathology with reduced cell surface expression and current. Notably, 4 transmembrane domain variants may distort channel conductance. Our research aligns with ACMG/AMP criteria PP3 and PM1.

Keywords

• GABA (A) receptor
• In silico
• Epilepsy
• Pathogenic variant
• Gamma-2 subunit
• Precision medicine

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