Sztuczna inteligencja w ocenie mutacji genetycznych związanych z epilepsją: Nauczeni na przykładzie receptorów GABA i transportera GABA 1

This review examines how recent genetic and technological advances have transformed our understanding and treatment of genetic epilepsies (GEs), with a focus on disorders involving GABA receptors (GABRs) and the GABA transporter 1 (GAT-1) encoded by SLC6A1. About 1000 genes are associated with epilepsy, including ~100 directly linked to defined epilepsy syndromes. Many disease-causing variants affect ion channels and transporters, disrupting protein structure, trafficking, and synaptic function. These defects often underlie developmental and epileptic encephalopathies (DEEs). A key insight from recent studies is that endoplasmic reticulum (ER)-related pathology-such as protein misfolding, ER retention, and accelerated degradation, which are common consequences of those pathogenic variants. For example, mutations in SLC6A1 or GABRG2 lead to impaired trafficking and reduced surface expression of GAT-1 or GABR subunits, resulting in deficient inhibitory neurotransmission. These mechanisms have been validated using advanced cellular assays and mouse models, although such experimental approaches remain costly and labor-intensive. Artificial intelligence (AI) is emerging as a powerful complement to experimental studies. Computational approaches, including generative AI and protein language models, can predict mutation-induced changes in protein structure, stability, and interactions, aided by tools such as AlphaFold. These methods enable large-scale, system-level analysis of variants and hold promise for accelerating drug discovery. However, current AI models are limited by fragmented datasets and the inherent complexity of biological systems. Integrating AI with experimental research offers a scalable strategy to translate mechanistic insights across genetic epilepsies (GEs). For instance, 4-phenylbutyrate (PBA), tested in SLC6A1 and GABRG2 epilepsy mouse models and now in clinical trials (NCT04937062), shows promise for treating GEs and DEEs caused by ER-retained mutant proteins. AI-based prediction could help identify additional GEs likely to respond to similar therapeutic approaches. Overall, combining experimental and AI-driven methods represents a new frontier for advancing the diagnosis and treatment of GEs and DEEs. PLAIN LANGUAGE SUMMARY: Mutations in almost 1000 genes have been linked to epilepsies, including those affecting GABA signaling such as GABAA receptors and the GABA transporter. Using cell and mouse studies, we found that many of these gene mutations cause similar problems inside cells. Specifically, the mutant proteins get stuck inside the cell in a structure called the endoplasmic reticulum (ER) and cause ER stress. Importantly, an FDA-approved drug 4-phenylbutyrate (PBA) can reduce these problems. We propose using artificial intelligence (AI) to predict how different gene mutations affect protein function and to identify which patients are likely to benefit from PBA treatment.