biostudies-literatureMao LNational Natural Science Foundation of China505https://www.ebi.ac.uk/biostudies/studies/S-EPMC10135792biostudies-literatureUnknown12(4)The <i>GJB2</i> gene is the most common gene responsible for hearing loss (HL) worldwide, and missense variants are the most abundant type. <i>GJB2</i> 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 <i>GJB2</i> 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, oligomerizationBiologyMolecular Mechanisms and Clinical Phenotypes of <i>GJB2</i> Missense Variants.PMC1013579282101963Zeng BFrishman DLiu MAn LChen YWang YTang WXu HMao LfalseMolecular Mechanisms and Clinical Phenotypes of <i>GJB2</i> Missense Variants.The <i>GJB2</i> gene is the most common gene responsible for hearing loss (HL) worldwide, and missense variants are the most abundant type. <i>GJB2</i> 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 <i>GJB2</i> 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, oligomerization2023-01-01T00:00:00Z2023 Mar2025-04-04T11:05:54.672Z2025-04-04T11:05:54.672ZS-EPMC101357923710670610.3390/biology12040505