The primary effect of G45E Cx26 mutation is to cause leaky GJ hemichannels when cells are bathed in normal [Ca2+]0. Our data showed that abnormally open hemichannels with resultant cell death, in addition to GJ and hemichannel uncoupling, is a novel molecular mechanism by which Cx26 mutations may result in hearing impairment. One plausible therapeutic strategy for this type of Cx mutation, therefore, is to manipulate [Ca2+]0 and/or the Ca-binding affinity of GJ hemichannels.

Mutations in connexins (Cxs), the constitutive protein subunits of gap junction (GJ) intercellular channels, are one of the most common human genetic defects that cause severe prelingual non-syndromic hearing impairments. Many subtypes of Cxs (e.g., Cxs 26, 29, 30, 31, 43) and pannexins (Panxs) are expressed in the cochlea where they contribute to the formation of a GJ-based intercellular communication network. Cx26 and Cx30 are the predominant cochlear Cxs and they co-assemble in most GJ plaques to form hybrid GJs. The cellular localization of specific Cx subtypes provides a basis for understanding the molecular structure of GJs and hemichannels in the cochlea. Information about the interactions among the various co-assembled Cx partners is critical to appreciate the functional consequences of various types of genetic mutations. In vitro studies of reconstituted GJs in cell lines have yielded surprisingly heterogeneous mechanisms of dysfunction caused by various Cx mutations. Availability of multiple lines of Cx-mutant mouse models has provided some insight into the pathogenesis processes in the cochlea of deaf mice. Here we summarize recent advances in understanding the structure and function of cochlear GJs and give a critical review of current findings obtained from both in vitro studies and mouse models on the mechanisms of Cx mutations that lead to cell death in the cochlea and hearing loss.

Interventions: Patients received 100 simultaneous bilateral posterior cricoarytenoid muscle botulinum toxin injections for isolated abductor spasmodic dysphonia over a 6-year period. Main Outcome Measures: Major and minor complications, injection dosing, and demographics. Results: The total bilateral botulinum toxin injection dose per session ranged from 2.50 to 7.50 U, and the average

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