Connexin Function and Mechanisms of Cx26 Deficiency Induced Hearing Loss

Grants and Contracts Details


Mutations of gap junction gene Cx26 (GJB2) cause the most of hereditary deafness and are responsible for >50% of cases of nonsyndromic hearing loss, ranging from profound congenital deafness at birth to mild, progressive late-onset hearing loss in childhood. Cochlear implant can restore hearing function indicating that the deafness pathology locates at the cochlea. In the cochlea, Cx26 and Cx30 extensively express in the cochlear supporting cells but not hair cells. Cx26 deficiency in mice can induce cochlear developmental disorders, hair cell degeneration, endocochlear potential reduction, and active cochlear amplification declining. We further found that the congenital deafness is associated with cochlear developmental disorders and hair cell degeneration, whereas progressive late-onset hearing loss is associated with active cochlear amplification declining even hair cells have no connexin expression. We also demonstrated that K+-recycling hypothesis is not the deafness mechanism for Cx26 deficiency. However, detailed cellular and molecular mechanisms for deafness remain unclear. In addition, little is known about pathological changes in the human cochlea. Lack of such information directly hampers developing efficient therapeutic interventions. Lack of such information is also a direct cause for failure to rescue hearing in the gene therapy. In this proposal, we will continually investigate Cx26 function and the cellular and molecular mechanisms of Cx26 deficiency induced hearing loss, in particular, mutation-induced pathologies in the human cochlea. We will first define how Cx26 deficiency causes degeneration of hair cells, which have no connexin expression. Anoikis is a matrix deprivation-induced cell apoptosis, caused by cell detaching from the surrounding extracellular matrix (ECM) or losing their surround ECM. It has been reported that connexin deficiency can impair ECM formation. We will test whether Cx26 deficiency can impair supporting cells’ ECM to cause hair cell anoikis degeneration. Secondly, we will define how Cx26 deficiency declines outer hair cell (OHC) electromotility and active cochlear amplification in late-onset hearing loss, which patients are good candidates for administration of preventive and therapeutic interventions due to normal hearing in their earlier life. We will test whether Cx26 deletion can impair cytoskeleton formation in the cochlear supporting cells, thereby altering OHC electromotility to reduce active cochlear amplification. Finally, we will define mutation-induced pathological changes in the human cochlea by backward-mutation screening, which we will screen Cx26 mutations in the archival human temporal bones from patients with hereditary hearing loss whose pathological changes in the cochlea have been diagnosed. Undoubtedly, these proposed studies will elucidate the detailed cellular and molecular mechanisms underlying Cx26 deficiency-induced hearing loss and mutation-induced pathological changes in the human cochlea. All of which is essential and required for developing efficient therapeutic interventions, particularly mutation-specific gene therapy.
Effective start/end date7/19/219/15/22


  • National Institute on Deafness & Other Communications


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