Diverse deafness mechanisms of connexin mutations revealed by studies using in vitro approaches and mouse models

• Type of Material: Article
• Authors: Emilie Hoang Dinh, Emory University; Shoeb Ahmad, Emory University; Qing Chang, Emory University; Wenxue Tang, Emory University; Benjamin C. Stong, Emory University; Xi Lin, Emory University
• Language: English
• Date: 2009-06-24
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009 Elsevier B.V. All rights reserved.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016/j.brainres.2009.02.008
• Title of Journal or Parent Work: Brain Research
• ISSN: 0006-8993
• Volume: 1277
• Start Page: 52
• End Page: 69
• Grant/Funding Information: W. Tang received grant supports from NIDCD (R21-DC008672) and deafness research foundation.; Shoeb Ahmad received a RO3 grant from NIDCD (RO3-DC008693).; Studies in Lin laboratory at Emory University are supported by grants to XL from NIDCD (RO1-DC006483 and R21-DC008353) and Woodruff foundation.
• Keywords: review; deafness mechanism; gap junction function; inherited deafness; connexin mutations
• Research Categories: Health Sciences, Audiology; Health Sciences, Medicine and Surgery

Abstract

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.