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

The Gap junction protein beta 2 (GJB2) R75W mutant genomic locus is a specific genetic target located on chromosome 13q12.11, where a cytosine-to-thymine transition (c.223C>T) results in an arginine-to-tryptophan substitution at position 75 of the Connexin 26 (Cx26) protein [1, 3]. In the mammalian cochlea, Cx26 is highly expressed in supporting cells, such as Deiters' cells and pillar cells, where it forms gap junction channels essential for recycling potassium ions from hair cells back to the endolymph [2, 4]. The R75W mutation is characterized by a potent dominant-negative effect, meaning the mutant protein not only fails to function but also poisons the assembly and activity of wild-type Cx26 hemichannels [2]. This disruption leads to the death of supporting cells and subsequent hair cell degeneration, manifesting as severe-to-profound autosomal dominant nonsyndromic hearing loss (DFNA3A) [3]. Therapeutic strategies targeting this locus primarily involve allele-specific gene editing, such as CRISPR-Cas9 systems, designed to selectively knock out the mutant allele while leaving the healthy wild-type allele intact to maintain sufficient gap junction function [2, 4]. This precision medicine approach aims to prevent the progressive hearing loss associated with the mutation by restoring the physiological ion homeostasis within the inner ear [4]. [1] UniProt Consortium. P29033. [2] György, B., et al. (2019). Nature Medicine. [3] OMIM. #121011. [4] Gao, X., et al. (2018). Nature.

Other names

Connexin 26 R75WCX26 R75WGJB2 c.223C>TDFNA3A genomic locusGap junction beta-2 protein R75W mutant

Allele-specific gene disruption or silencing to eliminate the dominant-negative effect of the mutant protein while preserving wild-type function.