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

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.

Timed conditional null of connexin26 in mice reveals temporary requirements of connexin26 in key cochlear developmental events before the onset of hearing

“…These mutations are the most common cause of genetic deafness in humans (Hilgert et al, 2009;Lin et al, 2012) and usually cochlear implants give excellent prognosis for these patients (Connell et al, 2007). However, the mechanisms of hearing loss resulting from the Cx26 mutations are unclear (Hoang Dinh et al, 2009). Previous studies mostly focused on GJ-mediated dysfunctions after onset of hearing, such as disruption of the pathway for K + recycling (Kikuchi et al, 2000) and apoptotic cell death in the organ of Corti (Cohen-Salmon et al, 2002).…”

Mutations in Cx30 that are linked to skin disease and non-syndromic hearing loss exhibit several distinct cellular pathologies

“…Mutations in the genes encoding Cx26, Cx30, Cx30.3 and Cx31, in particular, have been linked predominantly to hearing loss and various skin diseases (Di et al, 2001). Importantly, mutations in Cx30 and Cx26, the most predominant connexins in the inner ear (Hoang Dinh et al, 2009), are the leading cause of nearly half of the cases of inherited prelingual non-syndromic hearing loss (Bitner-Glindzicz, 2002;Chang et al, 2009;Schutz et al, 2010;Wang et al, 2011). In particular, seven distinct single amino acid substitutions in the first half of the coding sequence of Cx30 are responsible for hearing loss and/or skin disease.…”

Non-syndromic hereditary sensorineural hearing loss: review of the genes involved

“…71 Mutations in the GJB2 gene account for 30-50 per cent of all cases of childhood deafness, and 1-4 per cent of the average human population are estimated to be carriers. 70 Other connexins associated with non-syndromic hearing loss are connexin 31 (GJB3, DFNA2b/DFNB91) 72,73 and connexin 30 (GJB6, DFNA3b/DFNB1b). 74,75 KCNQ4 encodes a protein that forms a voltage-gated potassium channel.…”

“…These gap junctions are made up of specialised proteins called connexins, which are expressed in the supporting cells of the organ of Corti and the connective tissue of the spiral ligament. 70 This gap junction network is associated with the recycling of potassium ions needed for normal hearing. The first identified gene and most common cause of non-syndromic hearing loss is GJB2, which encodes connexin 26 (DFNA3a/DFNB1a).…”