New strategy for development of diseased mouse model of hereditary deafness and fundamental therapy based on molecular mechanisms

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Hereditary deafness affects about 1 in 2,000 children and mutations in the GJB2 gene are the major cause in various ethnic groups. GJB2 encodes connexin26, a putative channel component in cochlear gap junction. However, the pathogenesis of hearing loss caused by the GJB2 mutations remains obscure. The generation of a mouse model to study the function of connexin26 during hearing has been hampered by the fact that gjb2 knockout mice are embryonic lethal.First, we produced transgenic mice carrying a R75W mutation in the gjb2 gene, which was identified in a hereditary deafness pedigree and showed a deleterious dominant-negative effect. The R75W+mice showed severe hearing loss from an early stage of development. Histological analysis of the mutants revealed deformity of supporting cells, failure in the formation of the tunnel of Corti, and degeneration of sensory hair cells. Despite robust expression of the transgene, no obvious structural change was observed in the stria vascularis or spiral ligament that is rich in connexin26 and generates the endolymph. The high resting potential in cochlear endolymph essential for hair cell excitation was normally sustained (Hum Mol Genet 12:995-1004,2004).Another mouse model of gjb2 mutation in recessive form was generated by targeted disruption of gjb2 using Cre recombinase controlled by P0. Targeted disruption of Gjb2 caused profound deafness from birth but has never reach maturation. Apparent degeneration of the organ of Corti was recognized, together with presumably secondary reduction of numbers of spiral spiral ganglion cells. These findings confirmed a crucial role of Gjb2 in the cochlear function. These results indicate that the GJB2 mutation associated with sensorineural deafness affects the differentiation of supporting cells resulting in disorganization of the organ of Corti, rather than affecting endolymph homeostasis, in mice and probably in human.