Molecular Mechanisms and Clinical Phenotypes of GJB2 Missense Variants

SIMPLE SUMMARY: Hearing loss is the most common sensory impairment in humans. Globally, GJB2 is the most common responsible gene, with missense variants being the most frequent variant type. Pathogenic missense variants in the GJB2 gene cause isolated hearing loss and hearing loss combined with skin diseases. However, the mechanism by which different missense variants cause different hearing loss phenotypes is unknown. We have summarized 84 functionally studied missense variants and reviewed the clinical phenotypes and the molecular mechanisms that affected connexon and gap junction functions. We have also compiled a comprehensive dataset of GJB2 missense variants from public databases and published literature and found that over 2/3 of the GJB2 missense variants are currently classified as variants of uncertain significance. With the development of cutting-edge deep mutational scanning technology, we predict that the molecular mechanisms by which all missense variants of GJB2 lead to different clinical phenotypes will be elucidated. These gained insights will facilitate the use of genetic testing in the prevention and control of hearing loss. ABSTRACT: The GJB2 gene is the most common gene responsible for hearing loss (HL) worldwide, and missense variants are the most abundant type. GJB2 pathogenic missense variants cause nonsyndromic HL (autosomal recessive and dominant) and syndromic HL combined with skin diseases. However, the mechanism by which these different missense variants cause the different phenotypes is unknown. Over 2/3 of the GJB2 missense variants have yet to be functionally studied and are currently classified as variants of uncertain significance (VUS). Based on these functionally determined missense variants, we reviewed the clinical phenotypes and investigated the molecular mechanisms that affected hemichannel and gap junction functions, including connexin biosynthesis, trafficking, oligomerization into connexons, permeability, and interactions between other coexpressed connexins. We predict that all possible GJB2 missense variants will be described in the future by deep mutational scanning technology and optimizing computational models. Therefore, the mechanisms by which different missense variants cause different phenotypes will be fully elucidated.