Normal development, function and repair of the sensory epithelia in the inner ear are all dependent on gap junctional intercellular communication. Mutations in the connexin genes GJB2 and GJB6 (encoding CX26 and CX30) result in syndromic and non-syndromic deafness via various mechanisms. Clinical vestibular defects, however, are harder to connect with connexin dysfunction. Cx26 and Cx30 proteins are widely expressed in the epithelial and connective tissues of the cochlea, where they may form homomeric or heteromeric gap junction channels in a cell-specific and spatiotemporally complex fashion. Despite the study of mutant channels and animal models for both recessive and dominant autosomal deafness, it is still unclear why gap junctions are essential for auditory function, and why Cx26 and Cx30 do not compensate for each other in vivo. Cx26 appears to be essential for normal development of the auditory sensory epithelium, but may be dispensable during normal hearing. Cx30 appears to be essential for normal repair following sensory cell loss. The specific modes of intercellular signalling mediated by inner ear gap junction channels remain undetermined, but they are hypothesised to play essential roles in the maintenance of ionic and metabolic homeostasis in the inner ear. Recent studies have highlighted involvement of gap junctions in the transfer of essential second messengers between the non-sensory cells, and have proposed roles for hemichannels in normal hearing. Here, we summarise the current knowledge about the molecular and functional properties of inner ear gap junctions, and about tissue pathologies associated with connexin mutations.

/pdf/connexins-and-gap-junctions-in-the-inner-ear-it-s-not-just-5c5pwf1a71.pdf

Connexins and gap junctions in the inner ear--it's not just about K⁺ recycling.

https://www.med.upenn.edu/schererlab/user_docs/OrthmannMurphy_MCN2007.pdf

Loss-of-function GJA12/Connexin47 mutations cause Pelizaeus–Merzbacher-like disease

Oculodentodigital dysplasia (ODDD) is associated with at least 28 connexin43 (Cx43) mutations. We characterized four of these mutants; Q49K, L90V, R202H, and V216L. Populations of these GFP-tagged mutants were transported to the cell surface in Cx43-negative HeLa cells and Cx43-positive NRK cells. Dual patch-clamp functional analysis in N2A cells demonstrated that channels formed by each mutant have dramatically reduced conductance. Dye-coupling analysis revealed that each mutant exhibits a dominant-negative effect on wild-type Cx43. Since ODDD patients display skeletal abnormalities, we examined the effect of three other Cx43 mutants previously shown to exert dominant-negative effects on wild-type Cx43 (G21R, G138R, and G60S) in neonatal calvarial osteoblasts. Differentiation was unaltered by expression of these mutants as alkaline phosphatase activity and extent of culture mineralization were unchanged. This suggests that loss-of-function Cx43 mutants are insufficient to deter committed osteoblasts from...

https://www.tandfonline.com/doi/pdf/10.1080/15419060500514143

Functional characterization of oculodentodigital dysplasia-associated Cx43 mutants.

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

This review explores the association between GJB2 gene mutations, encoding connexin 26 (Cx26), and nonsyndromic hearing loss. Connexins are proteins that form intracellular membrane channels and regulate ion movement between contiguous fluid spaces. A family of autosomal gene mutations has been identified that lead to abnormal connexin expression within the inner ear that are associated with hearing loss. The exact mechanism by which this link is elicited remains unclear. We aim to highlight the clinically underestimated prevalence of GJB2 gene mutations, to explore the influential role of ethnic diversity in mutation frequency, and to provide a framework for hearing specialists in considering the differential diagnosis of nonsyndromic hearing loss. By linking an observed phenotype associated with abnormal Cx26 expression to the current understanding of the biological and genetic basis underlying it will allow a more accurate clinical description of associated hearing loss, and therefore enable more effec...

Connexin 26 mutations in autosomal recessive deafness disorders: A review

Mutations in the gene (GJB2) coding for Connexin 26 (Cx26) are responsible for genetic forms of sensorineural hearing loss. This article describes a family characterized by congenital profound hearing loss, inherited in an autosomal dominant fashion and associated to a R75Q substitution in Cx26. Cell transfection and fluorescence imaging, dye transfer experiments and dual patch clamp recording showed that the mutant completely prevents the formation of functional channels despite assembling into junctional plaques, in communication incompetent HeLa cells. The disease is not associated with palmar and plantar keratosis in any of the family members, suggesting that R75Q substitution is not sufficient for the development of the complete syndromic phenotype. The association of palmar and plantar keratosis with profound hearing loss may be dependent on genetic background, requiring a functional interaction between the mutated Cx26 and other epidermally expressed connexins.

Functional analysis of R75Q mutation in the gene coding for Connexin 26 identified in a family with nonsyndromic hearing loss

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Functional analysis of R75Q mutation in the gene coding for Connexin 26 identified in a family with nonsyndromic hearing loss