Gap junction protein beta 2 (GJB2) R75W genomic locus (GJB2 R75W)

The GJB2 R75W genomic locus refers to a specific mutation site within the Gap Junction Protein Beta 2 gene, which encodes the Connexin 26 (Cx26) protein. In the mammalian cochlea, Cx26 is primarily expressed in supporting cells where it forms gap junction channels essential for recycling potassium ions back to the endolymph, a process critical for hair cell function and hearing (UniProt P29033). The R75W mutation (a substitution of arginine with tryptophan at position 75) exerts a potent dominant-negative effect, where the mutant protein interferes with the assembly and function of wild-type connexins, leading to severe-to-profound hearing loss (PubMed 12566520). This genomic locus is a primary target for precision medicine interventions, such as CRISPR-Cas9 or base editing, designed to selectively disable or correct the mutant allele while sparing the wild-type copy (PubMed 31263252). Successful targeting in cochlear supporting cells aims to restore the gap junction network and prevent the degeneration of the organ of Corti. Current research focuses on using adeno-associated virus (AAV) vectors or lipid nanoparticles to deliver these gene-editing tools directly into the inner ear (PubMed 35714584). Therapeutic success is measured by the preservation of hair cells and the restoration of auditory sensitivity as determined by electrophysiological testing. Challenges include ensuring high specificity for the mutant allele to avoid haploinsufficiency of the wild-type protein.

Other names

Connexin 26 R75WCx26 R75WGJB2 c.223C>TDFNA3 locusGJB2 R75W mutation

Allele-specific disruption or correction of the mutant R75W allele to eliminate its dominant-negative effect on wild-type Connexin 26 proteins.