GJB2 Gene: Protein Product and Function
The GJB2 gene encodes connexin 26, a gap junction protein of the beta subunit class that functions in cell-to-cell diffusion and recycling of small molecules, particularly potassium ions, in the inner ear. 1, 2
Protein Structure and Assembly
Connexin 26 oligomerizes with five other connexin molecules to form a connexon (hemichannel); two connexons then combine to create a functional gap junction channel. 3 This assembly process is critical for establishing intercellular communication networks among supporting cells and fibrocytes in the mammalian cochlea. 4
Functional Mechanism in the Inner Ear
The protein operates through several key mechanisms:
Potassium ion recycling: Connexin 26 facilitates the circulation and recycling of potassium ions between cells in the cochlea, which is essential for maintaining the ionic homeostasis required for auditory transduction. 1, 2
Intercellular signaling: Rather than serving merely as passive conduits, gap junctions formed by connexin 26 participate in active intercellular signaling among nonsensory cells in the inner ear. 5
Endothelial barrier maintenance: The protein contributes to maintaining the endothelial barrier function in the stria vascularis, a highly vascularized structure critical for generating the endocochlear potential. 5
Material transfer and signal exchange: Connexin 26 enables the transfer of small molecules and electrical signals between adjacent cells, supporting the metabolic and functional coordination necessary for normal hearing. 6
Clinical Significance
GJB2 represents the single most important genetic cause of childhood deafness, accounting for approximately 50% of all autosomal recessive nonsyndromic hearing loss and 15-40% of all deaf individuals across diverse populations. 1, 2 The DFNB1 locus, which includes both GJB2 (connexin 26) and the closely related GJB6 gene (connexin 30), is responsible for this substantial disease burden. 1, 2
Pathogenic Mechanisms
When GJB2 mutations occur, they disrupt gap junction function at multiple levels:
Translation failure: Some mutations (M1V, P173R) prevent protein synthesis entirely. 4
Trafficking defects: Certain variants (F161S, R184P) produce protein that fails to reach the cell membrane properly. 4
Assembly disruption: Mutations like L90P and M34T interfere with hemichannel oligomerization, preventing functional gap junction formation. 4
Channel dysfunction: Even when channels form and localize correctly, some variants (p.E47K, p.E47Q, p.H100L, p.H100Y, p.R127L, p.M195L) fail to function normally as homo-oligomeric channels, though they may retain some function in hetero-oligomeric configurations. 7
More than 150 different deafness-causing variants have been identified in GJB2, though a few common mutations account for the majority of cases in most populations. 1, 2 The specific mutation spectrum varies by ethnicity, with 35delG being most prevalent in Caucasian populations. 2