Introduction:
Inherited retinal dystrophies (IRDs) represent a heterogeneous group of genetic disorders characterized by a progressive degeneration of photoreceptors and retinal function, leading to vision loss. Recent research emphasizes the importance of modifier genes in modulating disease phenotypes, with CACNG8, which encodes the TARP γ-8 auxiliary subunit of AMPA receptors, emerging as a potential player. TARP γ-8, essential in modulating AMPA receptor function, may influence neural signaling pathways critical for retinal health. This study integrates genetic, molecular, and structural approaches to elucidate CACNG8's role in IRDs, aligning with key themes of cellular signaling and proteasomal degradation.

Methods:
A cohort of patients diagnosed with IRDs was subjected to targeted genetic screening for CACNG8 variants. Genomic DNA was extracted and analyzed using Sanger sequencing. Computational tools such as AlphaFold3 facilitated molecular docking and 3D structural modeling of wild-type and mutant TARP γ-8 protein complexes. Comparative analyses assessed receptor–ligand binding dynamics, hydrogen bond networks, and structural integrity across various CACNG8 variants, such as p.Arg123Ter and p.Leu96Val-Val102Met. Additionally, in silico predictions evaluated potential disruptions in AMPA receptor signaling pathways.

Results:
This study identified several novel and known variants in CACNG8 associated with altered protein functionality. Structural analysis highlighted significant deviations in receptor–ligand interaction profiles, particularly in mutants like p.Leu96Val-Arg123Ter. These mutations disrupted hydrogen bonding and impaired receptor desensitization recovery, pivotal in retinal synaptic plasticity. Pathway analysis suggested a cascade of signaling defects linked to reduced proteasomal degradation efficiency and impaired protein quality control, likely contributing to neuroretinal degeneration.

Conclusions:
This study positions CACNG8 as a modifier gene within IRD pathophysiology, with specific variants correlating with altered AMPA receptor function and cellular signaling disruption. These findings provide a molecular basis for understanding IRD variability, highlighting the interplay between genetic and proteomic factors in shaping retinal pathology and resonating with emerging themes in cellular neurobiology.