The γ-Actin with pathogenic variants of sites on actin-binding proteins caused earlier onset and more malignant progressive hearing loss.

Abstract

Background: The γ-actin protein, encoded by the ACTG1 gene, is a critical cytoskeletal component in non-muscle cells. Mutations in ACTG1 are associated with autosomal dominant, progressive sensorineural hearing loss (HL), but clinical heterogeneity remains poorly understood.

Methods: We identified a novel missense variant, c.981C>G (p.Ile327Met; I327M), in a Chinese family with hereditary HL through whole exome sequencing. Functional analyses were performed to assess ACTG1 mRNA and protein expression, F-actin organisation and subcellular localisation. Structural modelling and electrostatic analysis were used to predict the impact of the I327M substitution. Additionally, we reviewed 35 published ACTG1-related families involving 82 patients to explore genotype-phenotype correlations.

Results: The I327M variant resulted in significantly reduced ACTG1 transcript and protein levels, accompanied by disrupted F-actin integrity in patient-derived peripheral blood mononuclear cells. Structural modelling suggested that the variant alters the electrostatic environment near the tropomyosin-binding interface, potentially compromising filament stability. Literature review and comparative analysis revealed that variants located within actin-binding protein (ABP) interaction sites were associated with an earlier onset and more severe progression of HL compared with those located outside ABP-binding domains.

Conclusion: The c.981C>G (p.Ile327Met) variant contributes to HL pathogenesis through dual mechanisms involving impaired gene expression and filament destabilisation. This study highlights the clinical relevance of variant location relative to ABP binding regions and provides new insights into genotype-phenotype relationships in ACTG1-associated HL.