GAS2 – Hearing Loss Disorder

GAS2 (GAS2) has been implicated in the pathogenesis of hearing loss disorder, an autosomal dominant sensorineural impairment. Genetic studies in diverse populations and functional assays converge on a mechanism whereby loss or truncation of GAS2 disrupts cytoskeletal organization in cochlear supporting cells, leading to progressive hearing decline.

In a cohort of 24 multiplex Malian families (12 consanguineous), whole-exome sequencing solved 75% (18/24) of cases, with 94.4% (17/18) harboring variants in known hearing impairment genes, including one family with biallelic GAS2 variants (PMID:39663698). Complementing this, a large Chinese pedigree displayed autosomal dominant inheritance of a novel heterozygous splice-site mutation c.616-2A>G, which fully segregated with late-onset, progressive nonsyndromic hearing loss (NSHL) (PMID:38956677).

The c.616-2A>G variant results in intron retention and production of a C-terminally truncated protein (GAS2^mu), establishing a recurrent loss-of-function allele in GAS2-related NSHL. This allele was the first to reach segregation-level evidence in an AD family, underpinning a dominant-negative or toxic gain-of-function mechanism.

Functional assessment in vivo demonstrated that GAS2 knockout mice exhibit disorganized and destabilized microtubule bundles in supporting cells of the cochlear duct, recapitulating human auditory phenotypes (PMID:38956677). Cellular assays revealed that GAS2^mu undergoes accelerated ubiquitin–proteasome–mediated degradation, and its expression promotes apoptosis via an increased Bcl-xS/Bcl-xL ratio, rather than a p53-dependent pathway.

Cryo-electron microscopy of the GAS2 CH3 domain bound to F-actin (2.8 Å) and the GAR domain bound to microtubules identified critical residues mediating dual cytoskeletal interactions. Biochemical studies confirmed that C-terminal dimerization of GAS2 is essential for bundling of F-actin and microtubules, and that C-terminal truncations abolish this activity, mirroring the effect of pathogenic variants (PMID:40169809).

Collectively, genetic segregation in multiple families and concordant mechanistic data from animal models and structural/biochemical experiments provide strong clinical validity for GAS2 in hearing loss disorder. GAS2 should be included in diagnostic gene panels for NSHL, with c.616-2A>G and similar loss-of-function variants deemed pathogenic.

References

• HGG advances • 2025 • Whole-exome sequencing reveals known and candidate genes for hearing impairment in Mali. PMID:39663698
• Human Genomics • 2024 • A novel variant in GAS2 is associated with autosomal dominant nonsyndromic hearing impairment in a Chinese family. PMID:38956677
• The EMBO journal • 2025 • Dimerization of GAS2 mediates crosslinking of microtubules and F-actin. PMID:40169809

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