Multifaceted disruption of AMPA receptor signaling by CACNG8 variants: Integrated evidence from human genetics and...

The Transmembrane AMPA Receptor Regulatory Protein Gamma-8 (TARP γ-8), encoded by CACNG8, regulates AMPA receptor (AMPAR) trafficking, gating, and synaptic localization. Although well-characterized in central synapses, its role in retinal development and disease remains underexplored. This study investigates CACNG8 within the context of inherited retinal dystrophies (IRDs) by integrating human genetics within silico structural analysis. Whole Exome Sequencing (WES) was performed on IRD-affected families with atypical phenotypes-such as residual photoreceptor activity alongside severe optic atrophy or abnormal electroretinogram (ERG) profiles-yet no biallelic mutations in known IRD genes. In all families, rare heterozygous or compound heterozygous CACNG8 variants were identified, including a recurrent stop-gain (p.Arg123Ter) and two missense variants (p.Leu96Val, p.Val102Met), suggesting a potential modifier role. To explore their functional impact, we modeled 14 AMPAR-associated postsynaptic complexes, comparing wild-type and mutant TARP γ-8 configurations. These included auxiliary subunits (CACNG2-7, CNIH2/3), scaffolding proteins (PSD93, PSD95), and regulators (PPP3CA, RIMBPs). Docking and MM-PBSA/MM-GBSA analyses revealed that truncation or destabilization of CACNG8 severely reduced complex stability (ΔΔG > 20 kcal/mol) and altered binding geometry. Molecular dynamics simulations highlighted increased structural perturbations, reduced hydrogen bonding, and greater conformational disorder in mutant assemblies. Grid Inhomogeneous Solvation Theory (GIST) and PCA/TICA analyses further revealed diminished water structuring and constrained conformational landscapes. Altogether, our findings support the potential role of CACNG8 as a genetic modifier in IRDs, pending further validation in larger cohorts. The study illustrates how combining genomic and structural approaches can uncover hidden contributors to complex retinal disorders.