SENSORINEURAL DEAFNESS AND CONNEXIN CHANNEL DYSFUNCTION

Permanent childhood deafness occurs with an incidence of ~1.5 cases per 1000 live births. Approximately 30% of deaf children have cognitive impairment due to the loss of functional interactions among the sensory systems. Although there are a number of genes associated with inherited deafness, mutation of the GJB2 gene encoding the Cx26 gap junction (GJ) protein is the most common. In addition to cognitive impairment and slowed development, there is growing evidence that some Cx26 mutations are linked to developmental cerebellar anomalies. Our studies are currently focusing on a subset of GJB2 mutations that lead to syndromic forms of deafness in which sensorineural hearing loss is accompanied by severe, inflammatory skin disorders, such as keratitis-ichthyosis-deafness (KID) syndrome. Some KID syndrome mutations result in fatality due to uncontrollable sepsis. The underlying basis of KID syndrome and other forms of syndromic deafness appears to be aberrantly behaving hemichannels, a relatively new mechanism identified among Cx-related disorders. Cx hemichannels do not participate in the formation of intercellular GJ channels, but rather remain undocked and function as large, ion channels in the plasma membrane. Mutant hemichannels have been described to behave in a "leaky" manner leading to compromised cell function and cell death. We use a combination of molecular, biophysical and imaging approaches to investigate the mechanisms by which Cx hemichannels are dysfunctional. Planned mouse models will examine contributions of hemichannels in native tissue and provide avenues for treatment.  Using explants of the organ of Corti we are examining how Cx channels, both WT and mutant, affect Ca²⁺ dynamics in the cochlea in early postnatal development, which is linked to maturation of hair cells, the principal sensory cells in the cochlea. In addition, we have initiated mathematical modeling of Cx channel gating to better understanding the behavior of Cxs in the cochlea, as well as in neural circuits, in general, where they serve to modulate excitability and coordinate electrical activity.

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Srinivas M, Calderon D. P., Kronengold J and Verselis VK (2006). Regulation of connexin hemichannels by monovalent cations. J Gen Phys 127:67-75. PMCID: PMC2151478

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