Gap Junctions and Connexins: The Molecular Genetics of Deafness

Abstract

Mutations in the gene GJB2 encoding the gap‐junction protein connexin 26 ( Cx26 ), in particular, and in GJB6 coding for connexin 30 ( Cx30 ) are the most common cause of autosomal recessive sensorineural hearing loss in many world populations. Variants of GJB2 are also associated with dominant forms of both nonsyndromic and syndromic deafness. A complex picture of the roles of gap junctions in cochlear physiology has emerged. Rather than being mere conduits for the circulation of potassium ions in the inner ear, gap junctions have been implicated in the maintenance of metabolic homeostasis and in intercellular signalling among nonsensory cells. Studies of mutant channels and mouse models for connexin ‐related deafness have provided valuable insights into the heterogeneous mechanisms by which connexin mutations may cause cochlear dysfunction. Despite recent advances it is still not fully understood what roles gap junctions play in the inner ear and how connexin mutations cause deafness. Key Concepts: GJB2 and GJB6 have been mapped to the DFNB1 locus, which accounts for up to 50% of all cases of autosomal recessive nonsyndromic hearing loss. Molecular genetic tests for DFNB1 should include DNA sequencing of the GJB2 exons and mutation analysis for GJB6 deletions. The identification of factors underlying the phenotypic variability of connexin‐related hearing loss may improve clinical diagnosis and genetic counselling. A better understanding of the role of gap‐junctional communication in the inner ear and the structure–function relationships of connexin proteins is required for the development of mechanism‐based treatments of connexin‐associated hearing loss.