Gap-Junction Channels Dysfunction in Deafness and Hearing Loss

Abstract

Gap-junction channels connect the cytoplasm of adjacent cells, allowing the diffusion of ions and small metabolites. They are formed at the appositional plasma membranes by a family of related proteins named connexins. Mutations in connexins 26, 31, 30, 32, and 43 have been associated with nonsyndromic or syndromic deafness. The majority of these mutations are inherited in an autosomal recessive manner, but a few of them have been associated with dominantly inherited hearing loss. Mutations in the connexin26 gene (GJB2) are the most common cause of genetic deafness. This review summarizes the most relevant and recent information about different mutations in connexin genes found in human patients, with emphasis on GJB2. The possible effects of the mutations on channel expression and function are discussed, in addition to their possible physiologic consequences for inner ear physiology. Finally, we propose that connexin channels (gap junctions and hemichannels) may be targets for age-related hearing loss induced by oxidative damage. Antioxid. Redox Signal. 11, 309-322. 309

Different functional consequences of two missense mutations in theGJB2gene associated with non-syndromic hearing loss

“…The major causative alleles, c.35delG and c.235delC, have been well characterized in many studies, and the carrier frequencies of these mutations vary in different ethnic populations (Park et al, 2000;Green et al, 1999;Han et al, 2008;Zelante et al, 1997). In addition, a number of novel GJB2 variants that contain amino acid substitutions have been identified in numerous genetic studies (Martinez et al, 2009, Connexin-Deafness Homepage: World Wide Web URL: http://davinci.crg.es/deafness/). These variants were predicted to be pathogenic since the mutations were only found in patients and the residues were highly conserved among different species.…”

“…Therefore, the dominant-negative effect of the p.D46E mutation may be due to defective docking of the two opposing connexin hemichannels. In many cases, mutations in extracellular domains are associated with dominant inheritance and syndromic phenotype, such as skin disorders and other ectodermal abnormalities (Deng et al, 2006;Martinez et al, 2009;Marziano et al, 2003;Matos et al, 2008;Melchionda et al, 2005;Sun et al, 2005). Two different mutations in the EC1 (p.W44C and p.W44S) have been reported to be associated with dominantly inherited nonsyndromic hearing loss and to exert a dominant-negative effect on gap junction permeability (Martin et al, 1999;Marziano et al, 2003).…”

Dissection of neuronal gap junction circuits that regulate social behavior in Caenorhabditis elegans

“…Electrical synapses also have essential roles in the developing brain, where they regulate the formation of chemical synapses (3)(4)(5). In humans, mutations that affect electrical synapses are associated with neurological conditions such as epilepsy, deafness, and peripheral neuropathies (6)(7)(8). However, it is difficult to study electrical synapses in detail because there are few simple functional assays or pharmacological tools that selectively target their activity.…”

Mechanism of gating by calcium in connexin hemichannels

“…It is widely accepted that hyperactive connexin hemichannels play pathological roles. For instance, several human connexin mutations that cause human pathologies produce exacerbated hemichannel activity at the plasma membrane, which has deleterious consequences (3)(4)(5). Similarly, in nongenetic pathologies, including ischemia and muscular dystrophy, there is strong evidence that opening of hemichannels enhances tissue damage (6)(7)(8).…”