Hearing loss and pathological changes in a mouse model harboring Gjb2 p.D50N variant

Area of Science:

• Genetics and Molecular Biology
• Otolaryngology
• Neuroscience

Background:

• The GJB2 gene (encoding Connexin26) is a major cause of hereditary hearing loss.
• Phenotypic heterogeneity in GJB2-related hearing loss is not fully understood.
• Existing mouse models often show severe hearing loss, failing to explain mild to moderate cases.

Purpose of the Study:

• To investigate the mechanism of mild to moderate hearing loss caused by GJB2 variants.
• To develop a novel mouse model for studying GJB2-related hearing loss heterogeneity.
• To explore the role of gap junction dysfunction in early-stage hearing impairment.

Main Methods:

• Generated a Gjb2^D50N/- mouse model using CRISPR-Cas9 and crossbreeding.
• Utilized Auditory Brainstem Response (ABR) testing to assess hearing thresholds.
• Performed pathological analysis, including gap junction plaque evaluation and 2-NBDG uptake assays in outer hair cells.

Main Results:

• Gjb2^D50N/- mice exhibited mild to moderate progressive hearing loss.
• Observed fragmentation of gap junction plaques and reduced glucose analog uptake in outer hair cells.
• No significant hair cell or spiral ganglion neuron loss was detected in early stages.

Conclusions:

• Early mild to moderate hearing loss from the GJB2 D50N variant may stem from impaired energy supply to outer hair cells due to gap junction dysfunction, not structural cochlear damage.
• This Gjb2^D50N/- mouse model is valuable for understanding hearing loss heterogeneity.
• The model provides a basis for developing therapeutic strategies for mild to moderate hearing loss.