{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:35:22Z","timestamp":1785418522467,"version":"3.56.0"},"reference-count":175,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T00:00:00Z","timestamp":1779840000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["1R21DC019476\u201301A1"],"award-info":[{"award-number":["1R21DC019476\u201301A1"]}]},{"award":["1R21DC019476\u201301A1"],"award-info":[{"award-number":["1R21DC019476\u201301A1"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mutations in gap junction protein \u03b2-2 (GJB2), encoding Connexin 26 (Cx26), are the most common genetic cause of hearing loss, responsible for up to 50% of inherited non-syndromic cases worldwide. This review covers Cx26 from three perspectives: protein structure, mutant disease mechanisms, and treatment approaches. Structurally, 12 Cx26 subunits assemble into a gap junction channel connecting neighboring cells, enabling exchange of ions and signaling molecules; activity is regulated by calcium, pH, and CO2. In the cochlea, Cx26 channels are required for the development of sound-sensing hair cells, maintenance of the electrical gradient needed for hearing, and energy supply during sound processing. GJB2 mutations cause hearing loss through three mechanisms, complete loss of functional protein, failure of channel assembly or membrane delivery, and abnormal channel gating, that damage cochlear cells. Severity ranges from profound congenital deafness to gradual decline, depending on which mutations are inherited. Gene therapy, genome editing, and pharmacological approaches are under investigation; cochlear implantation remains the current standard of care.<\/jats:p>","DOI":"10.3390\/ijms27114831","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T14:36:56Z","timestamp":1779892616000},"page":"4831","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Connexin 26 in Hearing Health and Disease: StructuralFoundations, Mutation Mechanisms, and Therapeutic Perspectives"],"prefix":"10.3390","volume":"27","author":[{"given":"Weihua","family":"Qiu","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23219, USA"},{"name":"Center for Drug Discovery, Virginia Commonwealth University, Richmond, VA 23219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6278-0200","authenticated-orcid":false,"given":"Kaelah","family":"Schneider","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23219, USA"},{"name":"Department of Chemistry, Virginia Commonwealth University, Richmond, VA 23219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7177-9603","authenticated-orcid":false,"given":"Youzhong","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23219, USA"},{"name":"Center for Drug Discovery, Virginia Commonwealth University, Richmond, VA 23219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,27]]},"reference":[{"key":"ref_1","unstructured":"GBD 2019 Hearing Loss Collaborators (2021). Hearing loss prevalence and years lived with disability, 1990\u20132019: Findings from the Global Burden of Disease Study 2019. Lancet, 397, 996\u20131009."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Sun, Y., Yi, Y., Huang, G., Jiang, S., Zhou, Y., Chen, H., and Wang, D. (2025). Temporal trends in prevalence and years of life lived with disability for hearing loss in China from 1990 to 2021: An analysis of the global burden of disease study 2021. Front. Public Health, 13.","DOI":"10.3389\/fpubh.2025.1538145"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1097\/AUD.0000000000001420","article-title":"Hearing Loss Prevalence, Years Lived with Disability, and Hearing Aid Use in the United States from 1990 to 2019: Findings from the Global Burden of Disease Study","volume":"45","author":"Haile","year":"2024","journal-title":"Ear Hear."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.1056\/NEJMra050700","article-title":"Newborn hearing screening\u2014A silent revolution","volume":"354","author":"Morton","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"16094","DOI":"10.1038\/nrdp.2016.94","article-title":"Congenital hearing loss","volume":"3","author":"Korver","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_6","unstructured":"Adam, M.P., Bick, S., and Mirzaa, G.M. (2026, April 19). GJB2-Related Autosomal Recessive Nonsyndromic Hearing Loss, GeneReviews\u00ae, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK1272\/."},{"key":"ref_7","unstructured":"Adam, M.P., Bick, S., and Mirzaa, G.M. (2026, April 19). Genetic Hearing Loss Overview, GeneReviews\u00ae, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK1434\/."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2213","DOI":"10.2741\/4046","article-title":"Autosomal recessive nonsyndromic deafness genes: A review","volume":"17","author":"Duman","year":"2012","journal-title":"Front. Biosci. (Landmark Ed.)"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.mrrev.2008.08.002","article-title":"Forty-six genes causing nonsyndromic hearing impairment: Which ones should be analyzed in DNA diagnostics?","volume":"681","author":"Hilgert","year":"2009","journal-title":"Mutat. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1007\/s00439-016-1648-8","article-title":"Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss","volume":"135","author":"Bierer","year":"2016","journal-title":"Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Morris, J.A., Gonzalez, T., Blanton, S.H., Angeli, S.I., and Liu, X.Z. (2026). GJB2-Related Hearing Loss: Genotype-Phenotype Correlations, Natural History, and Emerging Therapeutic Strategies. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27010491"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1038\/nature07869","article-title":"Structure of the connexin 26 gap junction channel at 3.5 A resolution","volume":"458","author":"Maeda","year":"2009","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Posukh, O.L., Maslova, E.A., Danilchenko, V.Y., Zytsar, M.V., and Orishchenko, K.E. (2023). Functional Consequences of Pathogenic Variants of the GJB2 Gene (Cx26) Localized in Different Cx26 Domains. Biomolecules, 13.","DOI":"10.3390\/biom13101521"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"RP93686","DOI":"10.7554\/eLife.93686.3","article-title":"Structures of wild-type and a constitutively closed mutant of connexin26 shed light on channel regulation by CO2","volume":"13","author":"Brotherton","year":"2024","journal-title":"eLife"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"8770","DOI":"10.1038\/ncomms9770","article-title":"An electrostatic mechanism for Ca2+-mediated regulation of gap junction channels","volume":"7","author":"Bennett","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1523\/JNEUROSCI.2251-16.2016","article-title":"Connexin-Mediated Signaling in Nonsensory Cells Is Crucial for the Development of Sensory Inner Hair Cells in the Mouse Cochlea","volume":"37","author":"Johnson","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"a033233","DOI":"10.1101\/cshperspect.a033233","article-title":"Inner Ear Connexin Channels: Roles in Development and Maintenance of Cochlear Function","volume":"9","author":"Mammano","year":"2019","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"976388","DOI":"10.3389\/fnmol.2022.976388","article-title":"Pathological mechanisms of connexin26-related hearing loss: Potassium recycling, ATP-calcium signaling, or energy supply?","volume":"15","author":"Chen","year":"2022","journal-title":"Front. Mol. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Vlajkovic, S.M., Suzuki-Kerr, H., and Nayagam, B.A. (2025). Cochlear Homeostasis in Sensorineural Hearing Loss: Mechanisms, Implications, and Therapeutic Prospects. Int. J. Mol. Sci., 27.","DOI":"10.20944\/preprints202511.0185.v1"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Jagielnicki, M., Kucharska, I., Bennett, B.C., Harris, A.L., and Yeager, M. (2024). Connexin Gap Junction Channels and Hemichannels: Insights from High-Resolution Structures. Biology, 13.","DOI":"10.3390\/biology13050298"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Wang, Y., Jin, Y., Zhang, Q., Xiong, Y., Gu, X., Zeng, S., and Chen, W. (2023). Research progress in delineating the pathological mechanisms of GJB2-related hearing loss. Front. Cell. Neurosci., 17.","DOI":"10.3389\/fncel.2023.1208406"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"107482","DOI":"10.1016\/j.celrep.2020.03.046","article-title":"A Steric \u201cBall-and-Chain\u201d Mechanism for pH-Mediated Regulation of Gap Junction Channels","volume":"31","author":"Khan","year":"2020","journal-title":"Cell Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.str.2022.02.010","article-title":"Conformational changes and CO2-induced channel gating in connexin26","volume":"30","author":"Brotherton","year":"2022","journal-title":"Structure"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e202413600","DOI":"10.1085\/jgp.202413600","article-title":"An Ala\/Glu difference in E1 of Cx26 and Cx30 contributes to their differential anionic permeabilities","volume":"156","author":"Kraujaliene","year":"2024","journal-title":"J. Gen. Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6495","DOI":"10.1073\/pnas.96.11.6495","article-title":"Formation of heteromeric gap junction channels by connexins 40 and 43 in vascular smooth muscle cells","volume":"96","author":"He","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3299","DOI":"10.1091\/mbc.e11-12-1058","article-title":"Critical role of the first transmembrane domain of Cx26 in regulating oligomerization and function","volume":"23","author":"Jara","year":"2012","journal-title":"Mol. Biol. Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1038\/s41586-018-0786-7","article-title":"Structure of native lens connexin 46\/50 intercellular channels by cryo-EM","volume":"564","author":"Myers","year":"2018","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.bbamem.2017.07.003","article-title":"Crucial motifs and residues in the extracellular loops influence the formation and specificity of connexin docking","volume":"1860","author":"Bai","year":"2018","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1038\/s41467-023-37040-8","article-title":"Cryo-EM structures of human Cx36\/GJD2 neuronal gap junction channel","volume":"14","author":"Lee","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1186\/s12964-023-01439-z","article-title":"Simulation of gap junction formation reveals critical role of Cys disulfide redox state in connexin hemichannel docking","volume":"22","author":"Simon","year":"2024","journal-title":"Cell Commun. Signal."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1083\/jcb.140.5.1187","article-title":"The pattern of disulfide linkages in the extracellular loop regions of connexin 32 suggests a model for the docking interface of gap junctions","volume":"140","author":"Foote","year":"1998","journal-title":"J. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1017\/S0033583501003705","article-title":"Emerging issues of connexin channels: Biophysics fills the gap","volume":"34","author":"Harris","year":"2001","journal-title":"Q. Rev. Biophys."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1016\/j.str.2021.05.010","article-title":"Cryo-EM structure of an open conformation of a gap junction hemichannel in lipid bilayer nanodiscs","volume":"29","author":"Khan","year":"2021","journal-title":"Structure"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"14","DOI":"10.12703\/r\/11-14","article-title":"Recent advances in connexin gap junction biology","volume":"11","author":"Lampe","year":"2022","journal-title":"Fac. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1111\/j.1460-9568.2005.04031.x","article-title":"Connexin26 is responsible for anionic molecule permeability in the cochlea for intercellular signalling and metabolic communications","volume":"21","author":"Zhao","year":"2005","journal-title":"Eur. J. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1242\/jcs.113.8.1365","article-title":"Selective permeability of different connexin channels to the second messenger inositol 1,4,5-trisphosphate","volume":"113","author":"Niessen","year":"2000","journal-title":"J. Cell Sci."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Peracchia, C. (2025). History of Gap Junction Architecture and Potential Role of Calmodulin in Channel Arrays. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms262311337"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Peracchia, C. (2020). Calmodulin-Mediated Regulation of Gap Junction Channels. Int. J. Mol. Sci., 21.","DOI":"10.37247\/PAMB.1.2020.37"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Koh, J.-Y., Affortit, C., Ranum, P.T., West, C., Walls, W.D., Yoshimura, H., Shao, J.Q., Mostaert, B., and Smith, R.J. (2023). Single-cell RNA-sequencing of stria vascularis cells in the adult Slc26a4(-\/-) mouse. BMC Med. Genom., 16.","DOI":"10.1186\/s12920-023-01549-0"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1038\/s41467-023-44612-1","article-title":"Mechanism of anion exchange and small-molecule inhibition of pendrin","volume":"15","author":"Wang","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"F1345","DOI":"10.1152\/ajprenal.00487.2006","article-title":"Loss of cochlear HCO3\u2212 secretion causes deafness via endolymphatic acidification and inhibition of Ca2+ reabsorption in a Pendred syndrome mouse model","volume":"292","author":"Wangemann","year":"2007","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/s00232-005-0832-x","article-title":"Gap junctions and cochlear homeostasis","volume":"209","author":"Zhao","year":"2006","journal-title":"J. Membr. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e04249","DOI":"10.7554\/eLife.04249","article-title":"Connexin26 hemichannels with a mutation that causes KID syndrome in humans lack sensitivity to CO2","volume":"3","author":"Meigh","year":"2014","journal-title":"eLife"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Abbott, A.C., Garc\u00eda, I.E., Villanelo, F., Flores-Mu\u00f1oz, C., Ceriani, R., Maripill\u00e1n, J., Novoa-Molina, J., Figueroa-Cares, C., P\u00e9rez-Acle, T., and S\u00e1ez, J.C. (2022). Expression of KID syndromic mutation Cx26S17F produces hyperactive hemichannels in supporting cells of the organ of Corti. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.1071202"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s00249-015-1093-y","article-title":"The styrene-maleic acid copolymer: A versatile tool in membrane research","volume":"45","author":"Scheidelaar","year":"2016","journal-title":"Eur. Biophys. J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1038\/nprot.2016.070","article-title":"A method for detergent-free isolation of membrane proteins in their local lipid environment","volume":"11","author":"Lee","year":"2016","journal-title":"Nat. Protoc."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4331","DOI":"10.1038\/s41467-020-18120-5","article-title":"Connexin-46\/50 in a dynamic lipid environment resolved by CryoEM at 1.9 A","volume":"11","author":"Flores","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"12985","DOI":"10.1073\/pnas.1812526115","article-title":"Structure and activity of lipid bilayer within a membrane-protein transporter","volume":"115","author":"Qiu","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"103130","DOI":"10.1016\/j.sbi.2025.103130","article-title":"Advances in native cell membrane nanoparticles system","volume":"94","author":"Qiu","year":"2025","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate structure prediction of biomolecular interactions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e70426","DOI":"10.1002\/pro.70426","article-title":"Modeling intrinsically disordered regions from AlphaFold2 to AlphaFold3","volume":"35","author":"Mehdiabadi","year":"2026","journal-title":"Protein Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"eadl2528","DOI":"10.1126\/science.adl2528","article-title":"Generalized biomolecular modeling and design with RoseTTAFold All-Atom","volume":"384","author":"Krishna","year":"2024","journal-title":"Science"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1016\/j.cell.2019.05.016","article-title":"Principles for Integrative Structural Biology Studies","volume":"177","author":"Rout","year":"2019","journal-title":"Cell"},{"key":"ref_54","unstructured":"Bruss, D.M., and Shohet, J.A. (2026). Neuroanatomy, Ear. StatPearls, StatPearls Publishing."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Beach, R., Abitbol, J.M., Allman, B.L., Esseltine, J.L., Shao, Q., and Laird, D.W. (2020). GJB2 Mutations Linked to Hearing Loss Exhibit Differential Trafficking and Functional Defects as Revealed in Cochlear-Relevant Cells. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.00215"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Liu, W., and Rask-Andersen, H. (2022). GJB2 and GJB6 gene transcripts in the human cochlea: A study using RNAscope, confocal, and super-resolution structured illumination microscopy. Front. Mol. Neurosci., 15.","DOI":"10.3389\/fnmol.2022.973646"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"eadf4144","DOI":"10.1126\/sciadv.adf4144","article-title":"Cx26 heterozygous mutations cause hyperacusis-like hearing oversensitivity and increase susceptibility to noise","volume":"9","author":"Liu","year":"2023","journal-title":"Sci. Adv."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Taylor, R.R., Jagger, D.J., and Forge, A. (2012). Defining the cellular environment in the organ of Corti following extensive hair cell loss: A basis for future sensory cell replacement in the Cochlea. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0030577"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1007\/s00441-014-2029-z","article-title":"Connexins and gap junctions in the inner ear\u2014it\u2019s not just about K(+) recycling","volume":"360","author":"Jagger","year":"2015","journal-title":"Cell Tissue Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1007\/s00441-008-0641-5","article-title":"Cellular characterization of Connexin26 and Connnexin30 expression in the cochlear lateral wall","volume":"333","author":"Liu","year":"2008","journal-title":"Cell Tissue Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1002\/cne.10916","article-title":"Gap junctions in the inner ear: Comparison of distribution patterns in different vertebrates and assessment of connexin composition in mammals","volume":"467","author":"Forge","year":"2003","journal-title":"J. Comp. Neurol."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Wingard, J.C., and Zhao, H.-B. (2015). Cellular and Deafness Mechanisms Underlying Connexin Mutation-Induced Hearing Loss\u2014A Common Hereditary Deafness. Front. Cell Neurosci., 9.","DOI":"10.3389\/fncel.2015.00202"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1097\/MOO.0b013e32830e20b0","article-title":"Gap junctions and connexins in the inner ear: Their roles in homeostasis and deafness","volume":"16","author":"Nickel","year":"2008","journal-title":"Curr. Opin. Otolaryngol. Head Neck Surg."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Sun, L., Gao, D., Chen, J., Hou, S., Li, Y., Huang, Y., Mammano, F., Chen, J., and Yang, J. (2022). Failure of Hearing Acquisition in Mice with Reduced Expression of Connexin 26 Correlates with the Abnormal Phasing of Apoptosis Relative to Autophagy and Defective ATP-Dependent Ca2+ Signaling in Kolliker\u2019s Organ. Front. Cell. Neurosci., 16.","DOI":"10.3389\/fncel.2022.816079"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.bbrc.2014.04.016","article-title":"Deafness induced by Connexin 26 (GJB2) deficiency is not determined by endocochlear potential (EP) reduction but is associated with cochlear developmental disorders","volume":"448","author":"Chen","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.bbrc.2009.05.023","article-title":"Targeted connexin26 ablation arrests postnatal development of the organ of Corti","volume":"385","author":"Wang","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.nbd.2014.09.005","article-title":"Timed conditional null of connexin26 in mice reveals temporary requirements of connexin26 in key cochlear developmental events before the onset of hearing","volume":"73","author":"Chang","year":"2015","journal-title":"Neurobiol. Dis."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/j.neuroscience.2014.10.061","article-title":"Connexin26 (GJB2) deficiency reduces active cochlear amplification leading to late-onset hearing loss","volume":"284","author":"Zhu","year":"2015","journal-title":"Neuroscience"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1016\/S0960-9822(02)00904-1","article-title":"Targeted ablation of connexin26 in the inner ear epithelial gap junction network causes hearing impairment and cell death","volume":"12","author":"Ott","year":"2002","journal-title":"Curr. Biol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/S0304-3940(98)00318-8","article-title":"Inwardly rectifying K+ currents in intermediate cells in the cochlea of gerbils: A possible contribution to the endocochlear potential","volume":"247","author":"Takeuchi","year":"1998","journal-title":"Neurosci. Lett."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s007950070001","article-title":"Potassium ion recycling pathway via gap junction systems in the mammalian cochlea and its interruption in hereditary nonsyndromic deafness","volume":"33","author":"Kikuchi","year":"2000","journal-title":"Med. Electron. Microsc."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1113\/jphysiol.2006.112888","article-title":"Supporting sensory transduction: Cochlear fluid homeostasis and the endocochlear potential","volume":"576","author":"Wangemann","year":"2006","journal-title":"J. Physiol."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Xu, J., and Nicholson, B.J. (2023). Divergence between Hemichannel and Gap Junction Permeabilities of Connexin 30 and 26. Life, 13.","DOI":"10.3390\/life13020390"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1786","DOI":"10.1038\/ncomms2806","article-title":"Active cochlear amplification is dependent on supporting cell gap junctions","volume":"4","author":"Zhu","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.neulet.2012.08.085","article-title":"Cell degeneration is not a primary causer for Connexin26 (GJB2) deficiency associated hearing loss","volume":"528","author":"Liang","year":"2012","journal-title":"Neurosci. Lett."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Zhao, H.-B. (2017). Hypothesis of K+-Recycling Defect Is Not a Primary Deafness Mechanism for Cx26 (GJB2) Deficiency. Front. Mol. Neurosci., 10.","DOI":"10.3389\/fnmol.2017.00162"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.biocel.2014.09.021","article-title":"Dynamin 2 interacts with connexin 26 to regulate its degradation and function in gap junction formation","volume":"55","author":"Xiao","year":"2014","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1086\/497996","article-title":"GJB2 mutations and degree of hearing loss: A multicenter study","volume":"77","author":"Snoeckx","year":"2005","journal-title":"Am. J. Hum. Genet."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1001\/archoto.2009.202","article-title":"Audiologic phenotype and progression in GJB2 (Connexin 26) hearing loss","volume":"136","author":"Kenna","year":"2010","journal-title":"Arch. Otolaryngol. Head Neck Surg."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"e2406510","DOI":"10.1002\/advs.202406510","article-title":"Viral-Mediated Connexin 26 Expression Combined with Dexamethasone Rescues Hearing in a Conditional Gjb2 Null Mice Model","volume":"12","author":"Wang","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"e13973","DOI":"10.1111\/acel.13973","article-title":"Degradation of cochlear Connexin26 accelerate the development of age-related hearing loss","volume":"22","author":"Xu","year":"2023","journal-title":"Aging Cell"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.redox.2018.08.002","article-title":"Cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of Nfr2 pathway","volume":"19","author":"Fetoni","year":"2018","journal-title":"Redox Biol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.bbrc.2014.08.063","article-title":"Reduced expression of Connexin26 and its DNA promoter hypermethylation in the inner ear of mimetic aging rats induced by d-galactose","volume":"452","author":"Wu","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1038\/s12276-020-0377-1","article-title":"Degradation and modification of cochlear gap junction proteins in the early development of age-related hearing loss","volume":"52","author":"Tajima","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"149326","DOI":"10.1016\/j.gene.2025.149326","article-title":"Mechanisms of congenital hearing loss caused by GJB2 gene mutations and current progress in gene therapy","volume":"946","author":"Ma","year":"2025","journal-title":"Gene"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"11157","DOI":"10.1038\/s41467-025-66110-2","article-title":"Cell-specific delivery of GJB2 restores auditory function in mouse models of DFNB1 deafness and mediates appropriate expression in NHP cochlea","volume":"16","author":"Ivanchenko","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"5801","DOI":"10.7150\/thno.112225","article-title":"Promotion of Cx26 mutants located in TM4 region for membrane translocation successfully rescued hearing loss","volume":"15","author":"Zong","year":"2025","journal-title":"Theranostics"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1021\/acsptsci.3c00056","article-title":"A Chemical Chaperone Restores Connexin 26 Mutant Activity","volume":"6","author":"Wang","year":"2023","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Paciello, F., Zorzi, V., Raspa, M., Scavizzi, F., Grassi, C., Mammano, F., and Fetoni, A.R. (2022). Connexin 30 deletion exacerbates cochlear senescence and age-related hearing loss. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.950837"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"61S","DOI":"10.1177\/0003489415575060","article-title":"Ethnic-specific spectrum of GJB2 and SLC26A4 mutations: Their origin and a literature review","volume":"124","author":"Tsukada","year":"2015","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1097\/00125817-200207000-00004","article-title":"GJB2 (connexin 26) variants and nonsyndromic sensorineural hearing loss: A HuGE review","volume":"4","author":"Kenneson","year":"2002","journal-title":"Genet. Med."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"E34\u201353","DOI":"10.1002\/lary.24332","article-title":"GJB2-associated hearing loss: Systematic review of worldwide prevalence, genotype, and auditory phenotype","volume":"124","author":"Chan","year":"2014","journal-title":"Laryngoscope"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"258","DOI":"10.3390\/genes14020399","article-title":"Global Distribution of Founder Variants Associated with Non-Syndromic Hearing Impairment","volume":"14","author":"Aboagye","year":"2023","journal-title":"Genes"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Shinagawa, J., Moteki, H., Nishio, S.-Y., Noguchi, Y., and Usami, S.-I. (2020). Haplotype Analysis of GJB2 Mutations: Founder Effect or Mutational Hot Spot?. Genes, 11.","DOI":"10.3390\/genes11030250"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Romanov, G.P., Smirnova, A.A., Zamyatin, V.I., Mukhin, A.M., Kazantsev, F.V., Pshennikova, V.G., Teryutin, F.M., Solovyev, A.V., Fedorova, S.A., and Posukh, O.L. (2022). Agent-Based Modeling of Autosomal Recessive Deafness 1A (DFNB1A) Prevalence with Regard to Intensity of Selection Pressure in Isolated Human Population. Biology, 11.","DOI":"10.3390\/biology11020257"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1002\/humu.23630","article-title":"Expert specification of the ACMG\/AMP variant interpretation guidelines for genetic hearing loss","volume":"39","author":"Oza","year":"2018","journal-title":"Hum. Mutat."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"198","DOI":"10.21053\/ceo.2023.00078","article-title":"Deficient Gap Junction Coupling in Two Common Hearing Loss-Related Variants of GJB2","volume":"17","author":"Chen","year":"2024","journal-title":"Clin. Exp. Otorhinolaryngol."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Lin, Y.-F., Chen, C.-H., Lee, C.-Y., Lin, H.-C., and Hsu, Y.-C. (2025). Mutation Spectrum of GJB2 in Taiwanese Patients with Sensorineural Hearing Loss: Prevalence, Pathogenicity, and Clinical Implications. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26178213"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"108135","DOI":"10.1016\/j.heares.2020.108135","article-title":"GJB2 mutation spectrum in the Taiwanese population and genotype-phenotype comparisons in patients with hearing loss carrying GJB2 c.109G>A and c.235delC mutations","volume":"413","author":"Lin","year":"2022","journal-title":"Hear. Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"e2185","DOI":"10.1002\/mgg3.2185","article-title":"Analysis of GJB2 gene mutations spectrum and the characteristics of individuals with c.109G>A in Western Guangdong","volume":"11","author":"Liang","year":"2023","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1038\/ejhg.2008.179","article-title":"Functional consequences of novel connexin 26 mutations associated with hereditary hearing loss","volume":"17","author":"Mani","year":"2009","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Mao, L., Wang, Y., An, L., Zeng, B., Wang, Y., Frishman, D., Liu, M., Chen, Y., Tang, W., and Xu, H. (2023). Molecular Mechanisms and Clinical Phenotypes of GJB2 Missense Variants. Biology, 12.","DOI":"10.3390\/biology12040505"},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Inoshita, A., Karasawa, K., Funakubo, M., Miwa, A., Ikeda, K., and Kamiya, K. (2014). Dominant negative connexin26 mutation R75W causing severe hearing loss influences normal programmed cell death in postnatal organ of Corti. BMC Genet., 15.","DOI":"10.1186\/1471-2156-15-1"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1034\/j.1399-0004.2001.590409.x","article-title":"W44C mutation in the connexin 26 gene associated with dominant non-syndromic deafness","volume":"59","author":"Tekin","year":"2001","journal-title":"Clin. Genet."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1097\/01.GIM.0000078026.01140.68","article-title":"Frequency and distribution of GJB2 (connexin 26) and GJB6 (connexin 30) mutations in a large North American repository of deaf probands","volume":"5","author":"Pandya","year":"2003","journal-title":"Genet. Med."},{"key":"ref_107","first-page":"862","article-title":"Homozygous M34T mutation of the GJB2 gene associates with an autosomal recessive nonsyndromic sensorineural hearing impairment in Finnish families","volume":"132","author":"Dietz","year":"2012","journal-title":"Acta Otolaryngol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"108597","DOI":"10.1016\/j.compbiomed.2024.108597","article-title":"Machine learning-based longitudinal prediction for GJB2-related sensorineural hearing loss","volume":"176","author":"Chen","year":"2024","journal-title":"Comput. Biol. Med."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1086\/301807","article-title":"Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss","volume":"62","author":"Kelley","year":"1998","journal-title":"Am. J. Hum. Genet."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1111\/ahg.12120","article-title":"Prevalence of Deafness-Associated Connexin-26 (GJB2) and Connexin-30 (GJB6) Pathogenic Alleles in a Large Patient Cohort from Eastern Sicily","volume":"79","author":"Amorini","year":"2015","journal-title":"Ann. Hum. Genet."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1055\/s-0042-1743257","article-title":"Analysis of Genetic Variations in Connexin 26 (GJB2) Gene among Nonsyndromic Hearing Impairment: Familial Study","volume":"9","author":"Hegde","year":"2022","journal-title":"Glob. Med. Genet."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1648","DOI":"10.1016\/j.ijporl.2014.07.014","article-title":"Frequency of GJB2 and del(GJB6-D13S1830) mutations among an Ecuadorian mestizo population","volume":"78","author":"Beaty","year":"2014","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1001\/archotol.131.6.481","article-title":"GJB2 and GJB6 mutations: Genotypic and phenotypic correlations in a large cohort of hearing-impaired patients","volume":"131","author":"Marlin","year":"2005","journal-title":"Arch. Otolaryngol. Head Neck Surg."},{"key":"ref_114","first-page":"70","article-title":"Etiologic Diagnosis of Genetic Hearing Loss in an Ethnically Diverse Deafness Cohort","volume":"30","author":"Yan","year":"2025","journal-title":"Audiol. Neurootol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1186\/s13256-024-04559-3","article-title":"Unusual phenotype in 35delG mutation: A case report","volume":"18","author":"Yeral","year":"2024","journal-title":"J. Med. Case Rep."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/sj.ejhg.5200406","article-title":"High carrier frequency of the 35delG deafness mutation in European populations. Genetic Analysis Consortium of GJB2 35delG","volume":"8","author":"Gasparini","year":"2000","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1007\/s00439-003-1018-1","article-title":"Evidence of a founder effect for the 235delC mutation of GJB2 (connexin 26) in east Asians","volume":"114","author":"Yan","year":"2003","journal-title":"Hum. Genet."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1097\/01.mlg.0000150691.85387.3f","article-title":"Common clinical features of children with enlarged vestibular aqueduct and Mondini dysplasia","volume":"115","author":"Wu","year":"2005","journal-title":"Laryngoscope"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1097\/01.GIM.0000066796.11916.94","article-title":"Mutation spectrum of the connexin 26 (GJB2) gene in Taiwanese patients with prelingual deafness","volume":"5","author":"Hwa","year":"2003","journal-title":"Genet. Med."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1097\/GIM.0b013e31804d2371","article-title":"The prevalence of the 235delC GJB2 mutation in a Chinese deaf population","volume":"9","author":"Dai","year":"2007","journal-title":"Genet. Med."},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Liu, Y., Wang, L., Yuan, L., Li, Y., Chen, Z., Yang, B., Wang, D., and Sun, Y. (2023). Hereditary deafness carrier screening in 9993 Chinese individuals. Front. Genet., 14.","DOI":"10.3389\/fgene.2023.1327258"},{"key":"ref_122","doi-asserted-by":"crossref","unstructured":"Teryutin, F.M., Pshennikova, V.G., Solovyev, A.V., Romanov, G.P., A Fedorova, S., and A Barashkov, N. (2024). Genotype-phenotype analysis of hearing function in patients with DFNB1A caused by the c.-23+1G>A splice site variant of the GJB2 gene (Cx26). PLoS ONE, 19.","DOI":"10.1371\/journal.pone.0309439"},{"key":"ref_123","doi-asserted-by":"crossref","unstructured":"Zytsar, M.V., Bady-Khoo, M.S., Danilchenko, V.Y., Maslova, E.A., Barashkov, N.A., Morozov, I.V., Bondar, A.A., and Posukh, O.L. (2020). High Rates of Three Common GJB2 Mutations c.516G>C, c.-23+1G>A, c.235delC in Deaf Patients from Southern Siberia Are Due to the Founder Effect. Genes, 11.","DOI":"10.3390\/genes11070833"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1056\/NEJM199811193392103","article-title":"Mutations in the connexin 26 gene (GJB2) among Ashkenazi Jews with nonsyndromic recessive deafness","volume":"339","author":"Morell","year":"1998","journal-title":"N. Engl. J. Med."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1006\/mgme.2001.3182","article-title":"Nonradioactive detection of the common Connexin 26 167delT and 35delG mutations and frequencies among Ashkenazi Jews","volume":"73","author":"Dong","year":"2001","journal-title":"Mol. Genet. Metab."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/1479-5876-7-26","article-title":"GJB2 mutation spectrum in 2063 Chinese patients with nonsyndromic hearing impairment","volume":"7","author":"Dai","year":"2009","journal-title":"J. Transl. Med."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1007\/s00439-021-02405-w","article-title":"A common founder effect of the splice site variant c.-23 + 1G > A in GJB2 gene causing autosomal recessive deafness 1A (DFNB1A) in Eurasia","volume":"141","author":"Solovyev","year":"2022","journal-title":"Hum. Genet."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"e39266","DOI":"10.1097\/MD.0000000000039266","article-title":"Novel GJB2 mutation c.188delT compound with c.235delC causing non-syndromic hearing loss in a Chinese family: A case report","volume":"103","author":"Tao","year":"2024","journal-title":"Medicine"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1097\/GIM.0b013e3181d0d42b","article-title":"Connexin-26-associated deafness: Phenotypic variability and progression of hearing loss","volume":"12","author":"Chan","year":"2010","journal-title":"Genet. Med."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1038\/s41392-023-01525-1","article-title":"Cx26 heterozygous mutations: Role in hyperacusis and vulnerability to noise","volume":"8","author":"Tawk","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/j.jmoldx.2023.07.005","article-title":"Genetic Factors Contribute to the Phenotypic Variability in GJB2-Related Hearing Impairment","volume":"25","author":"Chiang","year":"2023","journal-title":"J. Mol. Diagn."},{"key":"ref_132","first-page":"40","article-title":"Molecular basis of childhood deafness resulting from mutations in the GJB2 (connexin 26) gene","volume":"106","author":"Rabionet","year":"2000","journal-title":"Hum. Genet."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"2148","DOI":"10.1002\/ajmg.a.36042","article-title":"Homozygosity for the V37I GJB2 mutation in fifteen probands with mild to moderate sensorineural hearing impairment: Further confirmation of pathogenicity and haplotype analysis in Asian populations","volume":"161","author":"Gallant","year":"2013","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1007\/s00439-021-02376-y","article-title":"Hearing loss in Africa: Current genetic profile","volume":"141","author":"Adadey","year":"2022","journal-title":"Hum. Genet."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1038\/s41431-024-01711-x","article-title":"Targeted gene sequencing and hearing follow-up in 7501 newborns reveals an improved strategy for newborn hearing screening","volume":"33","author":"Hao","year":"2025","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"e24850","DOI":"10.1016\/j.heliyon.2024.e24850","article-title":"Carrier frequencies, trends, and geographical distribution of hearing loss variants in China: The pooled analysis of 2,161,984 newborns","volume":"10","author":"Feng","year":"2024","journal-title":"Heliyon"},{"key":"ref_137","doi-asserted-by":"crossref","unstructured":"Tang, X., Liu, L., Liang, S., Liang, M., Liao, T., Luo, S., Yan, T., and Chen, J. (2021). Concurrent Newborn Hearing and Genetic Screening in a Multi-Ethnic Population in South China. Front. Pediatr., 9.","DOI":"10.3389\/fped.2021.734300"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/gim.2016.66","article-title":"Newborn genetic screening for hearing impairment: A population-based longitudinal study","volume":"19","author":"Wu","year":"2017","journal-title":"Genet. Med."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1093\/hmg\/6.9.1605","article-title":"Connexin26 mutations associated with the most common form of non-syndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans","volume":"6","author":"Zelante","year":"1997","journal-title":"Hum. Mol. Genet."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1136\/jmg.37.1.41","article-title":"Prevalent connexin 26 gene (GJB2) mutations in Japanese","volume":"37","author":"Abe","year":"2000","journal-title":"J. Med. Genet."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1086\/339986","article-title":"Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis-ichthyosis-deafness syndrome","volume":"70","author":"Richard","year":"2002","journal-title":"Am. J. Hum. Genet."},{"key":"ref_142","first-page":"945","article-title":"Unveiling a novel GJB2 dominant K22T mutation in a Chinese family with hearing loss","volume":"56","author":"Ji","year":"2024","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_143","doi-asserted-by":"crossref","unstructured":"Namba, K., Mutai, H., Matsunaga, T., and Kaneko, H. (2024). Structural basis for pathogenic variants of GJB2 and hearing levels of patients with hearing loss. BMC Res. Notes, 17.","DOI":"10.1186\/s13104-024-06793-w"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/387080a0","article-title":"Connexin 26 mutations in hereditary non-syndromic sensorineural deafness","volume":"387","author":"Kelsell","year":"1997","journal-title":"Nature"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1097\/GIM.0b013e3180a03276","article-title":"A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort","volume":"9","author":"Putcha","year":"2007","journal-title":"Genet. Med."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"2369","DOI":"10.1093\/hmg\/8.13.2369","article-title":"Properties of connexin26 gap junctional proteins derived from mutations associated with non-syndromal heriditary deafness","volume":"8","author":"Martin","year":"1999","journal-title":"Hum. Mol. Genet."},{"key":"ref_147","doi-asserted-by":"crossref","unstructured":"Zonta, F., Buratto, D., Cassini, C., Bortolozzi, M., and Mammano, F. (2014). Molecular dynamics simulations highlight structural and functional alterations in deafness-related M34T mutation of connexin 26. Front. Physiol., 5.","DOI":"10.3389\/fphys.2014.00085"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"e202413675","DOI":"10.1085\/jgp.202413675","article-title":"Connecting the dots on connexin function","volume":"156","author":"Short","year":"2024","journal-title":"J. Gen. Physiol."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1085\/jgp.201310962","article-title":"The D50N mutation and syndromic deafness: Altered Cx26 hemichannel properties caused by effects on the pore and intersubunit interactions","volume":"142","author":"Sanchez","year":"2013","journal-title":"J. Gen. Physiol."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1097\/01.mlg.0000241944.77192.d2","article-title":"A novel mechanism for connexin 26 mutation linked deafness: Cell death caused by leaky gap junction hemichannels","volume":"116","author":"Stong","year":"2006","journal-title":"Laryngoscope"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1016\/S0006-291X(03)00868-4","article-title":"Permeability and gating properties of human connexins 26 and 30 expressed in HeLa cells","volume":"305","author":"Beltramello","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1085\/jgp.201210893","article-title":"Insights on the mechanisms of Ca2+ regulation of connexin26 hemichannels revealed by human pathogenic mutations (D50N\/Y)","volume":"142","author":"Lopez","year":"2013","journal-title":"J. Gen. Physiol."},{"key":"ref_153","doi-asserted-by":"crossref","unstructured":"Aypek, H., Bay, V., and Me\u015fe, G. (2016). Altered cellular localization and hemichannel activities of KID syndrome associated connexin26 I30N and D50Y mutations. BMC Cell Biol., 17.","DOI":"10.1186\/s12860-016-0081-0"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"21519","DOI":"10.1074\/jbc.M114.578757","article-title":"Altered inhibition of Cx26 hemichannels by pH and Zn2+ in the A40V mutation associated with keratitis-ichthyosis-deafness syndrome","volume":"289","author":"Sanchez","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"12824","DOI":"10.1038\/s41598-018-30757-3","article-title":"Roles of aberrant hemichannel activities due to mutant connexin26 in the pathogenesis of KID syndrome","volume":"8","author":"Taki","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1172\/JCI67621","article-title":"Assembly of the cochlear gap junction macromolecular complex requires connexin 26","volume":"124","author":"Kamiya","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"C613","DOI":"10.1152\/ajpcell.00341.2004","article-title":"Cochlear gap junctions coassembled from Cx26 and 30 show faster intercellular Ca2+ signaling than homomeric counterparts","volume":"288","author":"Sun","year":"2005","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_158","doi-asserted-by":"crossref","unstructured":"Zhou, X.-X., Chen, S., Xie, L., Ji, Y.-Z., Wu, X., Wang, W.-W., Yang, Q., Yu, J.-T., Sun, Y., and Lin, X. (2016). Reduced Connexin26 in the Mature Cochlea Increases Susceptibility to Noise-Induced Hearing Lossin Mice. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17030301"},{"key":"ref_159","unstructured":"Sutton, A.E., Krogmann, R.J., and Al Khalili, Y. (2026). Cochlear Implants. StatPearls, StatPearls Publishing."},{"key":"ref_160","doi-asserted-by":"crossref","unstructured":"Wu, X., Zhang, W., Li, Y., and Lin, X. (2019). Structure and Function of Cochlear Gap Junctions and Implications for the Translation of Cochlear Gene Therapies. Front. Cell. Neurosci., 13.","DOI":"10.3389\/fncel.2019.00529"},{"key":"ref_161","doi-asserted-by":"crossref","unstructured":"del Castillo, F.J., and del Castillo, I. (2017). DFNB1 Non-syndromic Hearing Impairment: Diversity of Mutations and Associated Phenotypes. Front. Mol. Neurosci., 10.","DOI":"10.3389\/fnmol.2017.00428"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/gt.2013.59","article-title":"Virally expressed connexin26 restores gap junction function in the cochlea of conditional Gjb2 knockout mice","volume":"21","author":"Yu","year":"2014","journal-title":"Gene Ther."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"3006","DOI":"10.1016\/j.ymthe.2025.03.029","article-title":"Combined AAV-mediated specific Gjb2 expression restores hearing in DFNB1 mouse models","volume":"33","author":"Sun","year":"2025","journal-title":"Mol. Ther."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"e185193","DOI":"10.1172\/jci.insight.185193","article-title":"AAV-mediated base editing restores cochlear gap junction in GJB2 dominant-negative mutation-associated syndromic hearing loss model","volume":"10","author":"Ukaji","year":"2025","journal-title":"JCI Insight"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"109552","DOI":"10.1016\/j.heares.2026.109552","article-title":"A porcine congenital deafness model with unconditional knockout of GJB2 generated by CRISPR\/Cas9 genomic editing","volume":"472","author":"Xie","year":"2026","journal-title":"Hear. Res."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1093\/bioinformatics\/btu048","article-title":"Cas-OFFinder: A fast and versatile algorithm that searches for potential off-target sites of Cas9 RNA-guided endonucleases","volume":"30","author":"Bae","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1038\/nbt.3117","article-title":"GUIDE-seq enables genome-wide profiling of off-target cleavage by CRISPR-Cas nucleases","volume":"33","author":"Tsai","year":"2015","journal-title":"Nat. Biotechnol."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1038\/nmeth.4278","article-title":"CIRCLE-seq: A highly sensitive in vitro screen for genome-wide CRISPR-Cas9 nuclease off-targets","volume":"14","author":"Tsai","year":"2017","journal-title":"Nat. Methods"},{"key":"ref_169","doi-asserted-by":"crossref","unstructured":"Lazzarotto, C.R., Katta, V., Li, Y., Manquen, G., Wood, R.K., Chyr, J., Urbina, E., Matsubara, A., Lee, G., and Wu, X. (2026). Sensitive and unbiased genome-wide profiling of base-editor-induced off-target activity using CHANGE-seq-BE. Nat. Biotechnol.","DOI":"10.1038\/s41587-025-02948-7"},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/s41589-022-01163-8","article-title":"Engineering a precise adenine base editor with minimal bystander editing","volume":"19","author":"Chen","year":"2023","journal-title":"Nat. Chem. Biol."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1093\/hmg\/ddi172","article-title":"In vitro and in vivo suppression of GJB2 expression by RNA interference","volume":"14","author":"Maeda","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"2662","DOI":"10.1016\/j.ymthe.2020.08.002","article-title":"Direct Delivery of Antisense Oligonucleotides to the Middle and Inner Ear Improves Hearing and Balance in Usher Mice","volume":"28","author":"Lentz","year":"2020","journal-title":"Mol. Ther."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/nm.3106","article-title":"Rescue of hearing and vestibular function by antisense oligonucleotides in a mouse model of human deafness","volume":"19","author":"Lentz","year":"2013","journal-title":"Nat. Med."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"6479","DOI":"10.1016\/j.ymthe.2025.08.044","article-title":"Antisense oligonucleotide therapy mitigates autosomal dominant progressive hearing loss in a murine model of human DFNA2","volume":"33","author":"Jang","year":"2025","journal-title":"Mol. Ther."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"108523","DOI":"10.1016\/j.heares.2022.108523","article-title":"Altering gene expression using antisense oligonucleotide therapy for hearing loss","volume":"426","author":"Robillard","year":"2022","journal-title":"Hear. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/4831\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T06:34:34Z","timestamp":1781073274000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/4831"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,27]]},"references-count":175,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ijms27114831"],"URL":"https:\/\/doi.org\/10.3390\/ijms27114831","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,27]]}}}