Hearing consequences in Gjb2 knock-in mice: implications for human p.V37I mutation

Area of Science:

• Genetics
• Otolaryngology
• Molecular Biology

Background:

• The GJB2 gene encodes connexin 26, crucial for gap junctions in the inner ear.
• The p.V37I mutation in GJB2 is linked to late-onset progressive hearing loss, particularly in East Asian populations.

Purpose of the Study:

• To create and characterize a mouse model mimicking the human GJB2 p.V37I-associated hearing loss.
• To investigate the underlying mechanisms of hearing impairment caused by this specific GJB2 mutation.

Main Methods:

• Generation of a knock-in mouse model with the human GJB2 p.V37I variant (c.109G>A).
• Auditory Brainstem Response (ABR) testing, cochlear pathology analysis, and electrophysiological recordings in inner hair cells (IHCs).
• Assessment of phenotype exacerbation following environmental insults (noise, KCl, furosemide).

Main Results:

• The mouse model recapitulated human progressive hearing loss without significant hair cell or neuron loss.
• Homozygous mice exhibited altered gap junction plaque length, a mild, lifelong endocochlear potential (EP) drop, and compromised cochlear amplification.
• Increased calcium currents (I_Ca) in IHCs and prolonged ABR wave I latencies were observed in aged homozygous mice.
• Environmental insults exacerbated the hearing loss phenotype.

Conclusions:

• GJB2 p.V37I mutation causes hearing loss via reduced cochlear amplification due to lowered EP.
• IHC excitotoxicity from potassium accumulation contributes to the hearing impairment.
• Environmental factors significantly accelerate the progression of this GJB2 mutation-induced hearing loss.