Abstract
Human p.V37I mutation of GJB2 gene was strongly correlated with late-onset progressive hearing loss, especially among East Asia populations. We generated a knock-in mouse model based on human p.V37I variant (c.109G>A) that recapitulated the human phenotype. Cochlear pathology revealed no significant hair cell loss, stria vascularis atrophy or spiral ganglion neuron loss, but a significant change in the length of gap junction plaques, which may have contributed to the observed mild endocochlear potential (EP) drop in homozygous mice lasting lifetime. The cochlear amplification in homozygous mice was compromised, but outer hair cells’ function remained unchanged, indicating that the reduced amplification was EP- rather than prestin-generated. In addition to ABR threshold elevation, ABR wave I latencies were also prolonged in aged homozygous animals. We found in homozygous IHCs a significant increase in ICa but no change in Ca2+ efficiency in triggering exocytosis. Environmental insults such as noise exposure, middle ear injection of KCl solution and systemic application of furosemide all exacerbated the pathological phenotype in homozygous mice. We conclude that this Gjb2 mutation-induced hearing loss results from 1) reduced cochlear amplifier caused by lowered EP, 2) IHCs excitotoxicity associated with potassium accumulation around hair cells, and 3) progression induced by environmental insults.
Highlights
Congenital hearing loss is the most common hereditary disease in human with a morbidity rate of 2-3‰ [1,2,3]
We conclude that this Gjb2 mutation-induced hearing loss results from 1) reduced cochlear amplifier caused by lowered endocochlear potential (EP), 2) inner hair cells (IHCs) excitotoxicity associated with potassium accumulation around hair cells, and 3) progression induced by environmental insults
GJB2 is expressed in inner ear supporting cells, stria vascularis, and spiral ligament; it is involved in a series of physiological processes of hearing including cochlear development, the generation of endocochlear potential (EP), active cochlear amplification, second messenger transduction and potassium recycling [10,11,12,13,14,15,16]
Summary
Congenital hearing loss is the most common hereditary disease in human with a morbidity rate of 2-3‰ [1,2,3]. Mutations in GJB2, which encodes connexin (Cx26) protein responsible for building up the gap junction (GJ) with connexin (Cx30) to form heterotypic GJ channels in the nonsensory epithelium in the cochlea, are among the most common disease causes [4,5,6,7,8,9]. Our previous studies found that p.V37I mutation of the GJB2 gene is related to a broad spectrum of hearing phenotypes in human. 65% of the patients with GJB2 p.V37I mutation had congenital hearing loss and the remaining 35% had a delayed disease onset. The degree of hearing loss varied in patients, ranging from normal hearing to profound hearing loss, with the severity of hearing loss strongly correlated with age [17, 18]
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