{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T02:26:31Z","timestamp":1783736791842,"version":"3.55.0"},"reference-count":184,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,10,13]],"date-time":"2023-10-13T00:00:00Z","timestamp":1697155200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Ministry of Education and Science of the Russian Federation","award":["FSUS-2020-0040"],"award-info":[{"award-number":["FSUS-2020-0040"]}]},{"name":"the Ministry of Education and Science of the Russian Federation","award":["FWNR-2022-0003"],"award-info":[{"award-number":["FWNR-2022-0003"]}]},{"name":"the Ministry of Education and Science of the Russian Federation","award":["FWNR-2022-0021"],"award-info":[{"award-number":["FWNR-2022-0021"]}]},{"name":"the Institute of Cytology and Genetics SB RAS","award":["FSUS-2020-0040"],"award-info":[{"award-number":["FSUS-2020-0040"]}]},{"name":"the Institute of Cytology and Genetics SB RAS","award":["FWNR-2022-0003"],"award-info":[{"award-number":["FWNR-2022-0003"]}]},{"name":"the Institute of Cytology and Genetics SB RAS","award":["FWNR-2022-0021"],"award-info":[{"award-number":["FWNR-2022-0021"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>One of the most common forms of genetic deafness has been predominantly associated with pathogenic variants in the GJB2 gene, encoding transmembrane protein connexin 26 (Cx26). The Cx26 molecule consists of an N-terminal domain (NT), four transmembrane domains (TM1\u2013TM4), two extracellular loops (EL1 and EL2), a cytoplasmic loop, and a C-terminus (CT). Pathogenic variants in the GJB2 gene, resulting in amino acid substitutions scattered across the Cx26 domains, lead to a variety of clinical outcomes, including the most common non-syndromic autosomal recessive deafness (DFNB1A), autosomal dominant deafness (DFNA3A), as well as syndromic forms combining hearing loss and skin disorders. However, for rare and poorly documented variants, information on the mode of inheritance is often lacking. Numerous in vitro studies have been conducted to elucidate the functional consequences of pathogenic GJB2 variants leading to amino acid substitutions in different domains of Cx26 protein. In this work, we summarized all available data on a mode of inheritance of pathogenic GJB2 variants leading to amino acid substitutions and reviewed published information on their functional effects, with an emphasis on their localization in certain Cx26 domains.<\/jats:p>","DOI":"10.3390\/biom13101521","type":"journal-article","created":{"date-parts":[[2023,10,13]],"date-time":"2023-10-13T06:07:26Z","timestamp":1697177246000},"page":"1521","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Functional Consequences of Pathogenic Variants of the GJB2 Gene (Cx26) Localized in Different Cx26 Domains"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1352-3591","authenticated-orcid":false,"given":"Olga L.","family":"Posukh","sequence":"first","affiliation":[{"name":"Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia"},{"name":"Novosibirsk State University, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5079-9787","authenticated-orcid":false,"given":"Ekaterina A.","family":"Maslova","sequence":"additional","affiliation":[{"name":"Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia"},{"name":"Novosibirsk State University, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5658-5974","authenticated-orcid":false,"given":"Valeriia Yu.","family":"Danilchenko","sequence":"additional","affiliation":[{"name":"Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia"},{"name":"Novosibirsk State University, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1219-9881","authenticated-orcid":false,"given":"Marina V.","family":"Zytsar","sequence":"additional","affiliation":[{"name":"Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9718-9038","authenticated-orcid":false,"given":"Konstantin E.","family":"Orishchenko","sequence":"additional","affiliation":[{"name":"Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia"},{"name":"Novosibirsk State University, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1002\/cphy.c110051","article-title":"Holstein-Rathlou NH. Gap junctions","volume":"2","author":"Nielsen","year":"2012","journal-title":"Compr. Physiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.bbamem.2003.11.022","article-title":"Selective permeability of gap junction channels","volume":"1662","author":"Goldberg","year":"2004","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1113\/jphysiol.2005.090985","article-title":"Connexin-specific cell-to-cell transfer of short interfering RNA by gap junctions","volume":"568","author":"Valiunas","year":"2005","journal-title":"J. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"15647","DOI":"10.1038\/srep15647","article-title":"Connexin26 gap junction mediates miRNA intercellular genetic communication in the cochlea and is required for inner ear development","volume":"5","author":"Zhu","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_5","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_6","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/S0092-8674(00)81282-9","article-title":"The gap junction communication channel","volume":"84","author":"Kumar","year":"1996","journal-title":"Cell"},{"key":"ref_7","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_8","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_9","doi-asserted-by":"crossref","first-page":"568","DOI":"10.12688\/f1000research.10490.1","article-title":"Gap junction structure: Unraveled, but not fully revealed","volume":"6","author":"Beyer","year":"2017","journal-title":"F1000Research"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"jkac062","DOI":"10.1093\/g3journal\/jkac062","article-title":"Connexinplexity: The spatial and temporal expression of connexin genes during vertebrate organogenesis","volume":"12","author":"Farnsworth","year":"2022","journal-title":"G3 (Bethesda)"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3189","DOI":"10.1242\/jcs.00604","article-title":"Specific amino-acid residues in the N-terminus and TM3 implicated in channel function and oligomerization compatibility of connexin43","volume":"116","author":"Lagree","year":"2003","journal-title":"J. Cell. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s00232-012-9443-5","article-title":"Cytoplasmic amino acids within the membrane interface region influence connexin oligomerization","volume":"245","author":"Smith","year":"2012","journal-title":"J. Membr. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.ceb.2004.07.014","article-title":"Connexins: Functions without junctions","volume":"16","author":"Stout","year":"2004","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.bbamem.2005.01.014","article-title":"Connexin-based gap junction hemichannels: Gating mechanisms","volume":"1711","author":"Retamal","year":"2005","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"18724","DOI":"10.1073\/pnas.0506481102","article-title":"Gap junctional hemichannel-mediated ATP release and hearing controls in the inner ear","volume":"102","author":"Zhao","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1016\/j.febslet.2014.03.004","article-title":"Hunting for connexin hemichannels","volume":"588","author":"Leybaert","year":"2014","journal-title":"FEBS Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.neulet.2017.09.020","article-title":"Connexin hemichannels and cochlear function","volume":"695","author":"Verselis","year":"2019","journal-title":"Neurosci. Lett."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Natha, C.M., Vemulapalli, V., Fiori, M.C., Chang, C.T., and Altenberg, G.A. (2021). Connexin hemichannel inhibitors with a focus on aminoglycosides. Biochim. Biophys. Acta Mol. Basis. Dis., 1867.","DOI":"10.1016\/j.bbadis.2021.166115"},{"key":"ref_19","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_20","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.bbamem.2003.10.017","article-title":"Connexin disorders of the ear, skin, and lens","volume":"1662","author":"Gerido","year":"2004","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.clindermatol.2004.09.010","article-title":"Connexin disorders of the skin","volume":"23","author":"Richard","year":"2005","journal-title":"Clin. Dermatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1042\/BJ20051922","article-title":"Life cycle of connexins in health and disease","volume":"394","author":"Laird","year":"2006","journal-title":"Biochem. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1042\/BJ20110278","article-title":"Key functions for gap junctions in skin and hearing","volume":"438","author":"Scott","year":"2011","journal-title":"Biochem. J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.abb.2012.03.008","article-title":"Biological role of connexin intercellular channels and hemichannels","volume":"524","author":"Kar","year":"2012","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.bbamem.2012.06.024","article-title":"The role of connexins in ear and skin physiology\u2014Functional insights from disease-associated mutations","volume":"1828","author":"Xu","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1007\/s00441-014-2024-4","article-title":"Mechanisms linking connexin mutations to human diseases","volume":"360","author":"Kelly","year":"2015","journal-title":"Cell Tissue Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"267","DOI":"10.3389\/fncel.2015.00267","article-title":"Diseases associated with leaky hemichannels","volume":"9","author":"Retamal","year":"2015","journal-title":"Front. Cell. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Garc\u00eda, I.E., Prado, P., Pupo, A., Jara, O., Rojas-G\u00f3mez, D., Mujica, P., Flores-Mu\u00f1oz, C., Gonz\u00e1lez-Casanova, J., Soto-Riveros, C., and Pinto, B.I. (2016). Connexinopathies: A structural and functional glimpse. BMC Cell Biol., 17.","DOI":"10.1186\/s12860-016-0092-x"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Iyyathurai, J., Decuypere, J.P., Leybaert, L., D\u2019hondt, C., and Bultynck, G. (2016). Connexins: Substrates and regulators of autophagy. BMC Cell Biol., 17.","DOI":"10.1186\/s12860-016-0093-9"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.bbamem.2017.04.024","article-title":"Human diseases associated with connexin mutations","volume":"1860","author":"Srinivas","year":"2018","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Rusiecka, O.M., Montgomery, J., Morel, S., Batista-Almeida, D., Van Campenhout, R., Vinken, M., Girao, H., and Kwak, B.R. (2020). Canonical and Non-Canonical Roles of Connexin43 in Cardioprotection. Biomolecules, 10.","DOI":"10.3390\/biom10091225"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Garcia-Vega, L., O\u2019Shaughnessy, E.M., Albuloushi, A., and Martin, P.E. (2021). Connexins and the Epithelial Tissue Barrier: A Focus on Connexin 26. Biology, 10.","DOI":"10.3390\/biology10010059"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Peng, B., Xu, C., Wang, S., Zhang, Y., and Li, W. (2022). The Role of Connexin Hemichannels in Inflammatory Diseases. Biology, 11.","DOI":"10.3390\/biology11020237"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1126\/science.283.5405.1176","article-title":"Three-dimensional structure of a recombinant gap junction membrane channel","volume":"283","author":"Unger","year":"1999","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"10034","DOI":"10.1073\/pnas.0703704104","article-title":"Three-dimensional structure of a human connexin26 gap junction channel reveals a plug in the vestibule","volume":"104","author":"Oshima","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Pantano, S., Zonta, F., and Mammano, F. (2008). A fully atomistic model of the Cx32 connexon. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0002614"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1007\/s00018-010-0551-z","article-title":"Structure of the gap junction channel and its implications for its biological functions","volume":"68","author":"Maeda","year":"2011","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1006\/abbi.2000.1989","article-title":"Structure of the amino terminus of a gap junction protein","volume":"381","author":"Purnick","year":"2000","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1085\/jgp.201110679","article-title":"Molecular dynamics simulations of the Cx26 hemichannel: Evaluation of structural models with Brownian dynamics","volume":"138","author":"Kwon","year":"2011","journal-title":"J. Gen. Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1016\/j.bbamem.2011.10.011","article-title":"Structural organization of intercellular channels II. Amino terminal domain of the connexins: Sequence, functional roles, and structure","volume":"1818","author":"Beyer","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1080\/073911012010525027","article-title":"Permeation pathway of homomeric connexin 26 and connexin 30 channels investigated by molecular dynamics","volume":"29","author":"Zonta","year":"2012","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/1478-811X-11-15","article-title":"The 3.5 \u00e5ngstr\u00f6m X-ray structure of the human connexin26 gap junction channel is unlikely that of a fully open channel","volume":"11","author":"Zonta","year":"2013","journal-title":"Cell Commun. Signal."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.abb.2016.06.019","article-title":"Structural studies of N-terminal mutants of Connexin 26 and Connexin 32 using (1)H NMR spectroscopy","volume":"608","author":"Batir","year":"2016","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.compbiolchem.2018.11.004","article-title":"Calcium interactions with Cx26 hemmichannel: Spatial association between MD simulations biding sites and variant pathogenicity","volume":"77","author":"Albano","year":"2018","journal-title":"Comput. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1089\/ars.2008.2138","article-title":"Gap-junction channels dysfunction in deafness and hearing loss","volume":"11","author":"Figueroa","year":"2009","journal-title":"Antioxid. Redox. Signal."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"162","DOI":"10.3389\/fnmol.2017.00162","article-title":"Hypothesis of K+-Recycling Defect Is Not a Primary Deafness Mechanism for Cx26 (GJB2) Deficiency","volume":"10","author":"Zhao","year":"2017","journal-title":"Front. Mol. Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Aasen, T., Johnstone, S., Vidal-Brime, L., Lynn, K.S., and Koval, M. (2018). Connexins: Synthesis, Post-Translational Modifications, and Trafficking in Health and Disease. Int. J. Mol. Sci., 19.","DOI":"10.20944\/preprints201803.0168.v1"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1016\/j.molmed.2018.10.005","article-title":"Therapeutic Targeting of Connexin Channels: New Views and Challenges","volume":"24","author":"Delvaeye","year":"2018","journal-title":"Trends Mol. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"529","DOI":"10.3389\/fncel.2019.00529","article-title":"Structure and Function of Cochlear Gap Junctions and Implications for the Translation of Cochlear Gene Therapies","volume":"13","author":"Wu","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"ref_50","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_51","doi-asserted-by":"crossref","unstructured":"Zhu, Y. (2022). Gap Junction-Dependent and -Independent Functions of Connexin43 in Biology. Biology, 11.","DOI":"10.3390\/biology11020283"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.heares.2009.01.010","article-title":"Unique expression of connexins in the human cochlea","volume":"250","author":"Liu","year":"2009","journal-title":"Hear. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1007\/s004410051192","article-title":"Expression of the gap-junction connexins 26 and 30 in the rat cochlea","volume":"294","author":"Lautermann","year":"1998","journal-title":"Cell Tissue Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.1097\/00001756-200008030-00022","article-title":"Expression of connexin 31 in the developing mouse cochlea","volume":"11","author":"Xia","year":"2000","journal-title":"Neuroreport"},{"key":"ref_55","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 assessement of connexin composition in mammals","volume":"467","author":"Forge","year":"2003","journal-title":"J. Comp. Neurol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s00441-004-0861-2","article-title":"Expression of the connexin43- and connexin45-encoding genes in the developing and mature mouse inner ear","volume":"316","author":"Maxeiner","year":"2004","journal-title":"Cell Tissue Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/S0006-291X(03)01166-5","article-title":"Connexins 26 and 30 are co-assembled to form gap junctions in the cochlea of mice","volume":"307","author":"Ahmad","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_58","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_59","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1016\/0092-8674(93)90728-9","article-title":"Multisubunit assembly of an integral plasma membrane channel protein, gap junction connexin43, occurs after exit from the ER","volume":"74","author":"Musil","year":"1993","journal-title":"Cell"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"21115","DOI":"10.1074\/jbc.M412612200","article-title":"Defining a minimal motif required to prevent connexin oligomerization in the endoplasmic reticulum","volume":"280","author":"Maza","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2593","DOI":"10.1091\/mbc.e08-07-0790","article-title":"ERp29 restricts Connexin43 oligomerization in the endoplasmic reticulum","volume":"20","author":"Das","year":"2009","journal-title":"Mol. Biol. Cell"},{"key":"ref_62","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_63","doi-asserted-by":"crossref","first-page":"3845","DOI":"10.1242\/jcs.114.21.3845","article-title":"Multiple pathways in the trafficking and assembly of connexin 26, 32 and 43 into gap junction intercellular communication channels","volume":"114","author":"Martin","year":"2001","journal-title":"J. Cell Sci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"4451","DOI":"10.1242\/jcs.02569","article-title":"Mechanisms of Cx43 and Cx26 transport to the plasma membrane and gap junction regeneration","volume":"118","author":"Thomas","year":"2005","journal-title":"J. Cell Sci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.heares.2019.01.020","article-title":"Actin-independent trafficking of cochlear connexin 26 to non-lipid raft gap junction plaques","volume":"374","author":"Defourny","year":"2019","journal-title":"Hear. Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"808553","DOI":"10.3389\/fnmol.2021.808553","article-title":"F-Actin Dysplasia Involved in Organ of Corti Deformity in GJB2 Knockdown Mouse Model","volume":"14","author":"Liu","year":"2022","journal-title":"Front. Mol. Neurosci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1016\/j.yexcr.2009.03.001","article-title":"The role of the cytoskeleton in the formation of gap junctions by Connexin 30","volume":"315","author":"Qu","year":"2009","journal-title":"Exp. Cell Res."},{"key":"ref_68","first-page":"93","article-title":"Proteins and mechanisms regulating gap-junction assembly, internalization, and degradation","volume":"28","author":"Kowal","year":"2013","journal-title":"Physiology (Bethesda)"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/j.bbamem.2013.07.006","article-title":"Influence of the scaffolding protein Zonula Occludens (ZOs) on membrane channels","volume":"1838","author":"Derangeon","year":"2014","journal-title":"Biochim. Biophys. Acta."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1002\/dvdy.538","article-title":"Recent insights into gap junction biogenesis in the cochlea","volume":"252","author":"Defourny","year":"2023","journal-title":"Dev. Dyn."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1042\/BJ20091140","article-title":"Post-translational modifications of connexin26 revealed by mass spectrometry","volume":"424","author":"Locke","year":"2009","journal-title":"Biochem. J."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Batissoco, A.C., Salazar-Silva, R., Oiticica, J., Bento, R.F., Mingroni-Netto, R.C., and Haddad, L.A. (2018). A Cell Junctional Protein Network Associated with Connexin-26. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19092535"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"202","DOI":"10.3389\/fncel.2015.00202","article-title":"Cellular and Deafness Mechanisms Underlying Connexin Mutation-Induced Hearing Loss\u2014A Common Hereditary Deafness","volume":"9","author":"Wingard","year":"2015","journal-title":"Front. Cell. Neurosci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"428","DOI":"10.3389\/fnmol.2017.00428","article-title":"DFNB1 Non-syndromic Hearing Impairment: Diversity of Mutations and Associated Phenotypes","volume":"10","year":"2017","journal-title":"Front. Mol. Neurosci."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Qiu, Y., Zheng, J., Chen, S., and Sun, Y. (2022). Connexin Mutations and Hereditary Diseases. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23084255"},{"key":"ref_76","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_77","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s00439-022-02479-0","article-title":"Comprehensive interpretation of single-nucleotide substitutions in GJB2 reveals the genetic and phenotypic landscape of GJB2-related hearing loss","volume":"142","author":"Xiang","year":"2023","journal-title":"Hum. Genet."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"28958","DOI":"10.1074\/jbc.M605764200","article-title":"The structural context of disease-causing mutations in gap junctions","volume":"281","author":"Fleishman","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1007\/s12013-014-0385-7","article-title":"Bioinformatic Analysis of GJB2 Gene Missense Mutations","volume":"71","author":"Yilmaz","year":"2015","journal-title":"Cell Biochem. Biophys."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.semcdb.2015.11.015","article-title":"Structural analysis of key gap junction domains--Lessons from genome data and disease-linked mutants","volume":"50","author":"Bai","year":"2016","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1007\/s00439-015-1625-7","article-title":"The pathological effects of connexin 26 variants related to hearing loss by in silico and in vitro analysis","volume":"135","author":"Kim","year":"2016","journal-title":"Hum. Genet."},{"key":"ref_82","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_83","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/j.ajhg.2018.08.006","article-title":"Genomic Landscape and Mutational Signatures of Deafness-Associated Genes","volume":"103","author":"Azaiez","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"ref_84","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_85","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1007\/s00439-004-1142-6","article-title":"Altered gating properties of functional Cx26 mutants associated with recessive non-syndromic hearing loss","volume":"115","author":"Londin","year":"2004","journal-title":"Hum. Genet."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"C966","DOI":"10.1152\/ajpcell.00008.2008","article-title":"Connexin26 deafness associated mutations show altered permeability to large cationic molecules","volume":"295","author":"Valiunas","year":"2008","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1007\/s00424-016-1788-7","article-title":"Gap-junctional channel and hemichannel activity of two recently identified connexin 26 mutants associated with deafness","volume":"468","author":"Dalamon","year":"2016","journal-title":"Pflugers Arch."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/S0006-291X(02)00891-4","article-title":"Hearing loss: Frequency and functional studies of the most common connexin26 alleles","volume":"296","author":"Veronesi","year":"2002","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.1038\/jid.2015.20","article-title":"Keratitis-ichthyosis-deafness syndrome-associated Cx26 mutants produce nonfunctional gap junctions but hyperactive hemichannels when co-expressed with wild type Cx43","volume":"135","author":"Jara","year":"2015","journal-title":"J. Investig. Dermatol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1002\/humu.9464","article-title":"Deficient membrane integration of the novel p.N14D-GJB2 mutant associated with non-syndromic hearing impairment","volume":"27","author":"Haack","year":"2006","journal-title":"Hum. Mutat."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.bbrc.2010.03.098","article-title":"Connexin 26 (GJB2) mutations as a cause of the KID syndrome with hearing loss","volume":"395","author":"Terrinoni","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1016\/j.bbrc.2010.03.073","article-title":"Connexin 26 (GJB2) mutations, causing KID Syndrome, are associated with cell death due to calcium gating deregulation","volume":"394","author":"Terrinoni","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Bailey, R.A., Beahm, D.L., and Skerrett, I.M. (2021). The Complex and Critical Role of Glycine 12 (G12) in Beta-Connexins of Human Skin. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052615"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1038\/jid.2008.335","article-title":"Connexin mutations causing skin disease and deafness increase hemichannel activity and cell death when expressed in Xenopus oocytes","volume":"129","author":"Lee","year":"2009","journal-title":"J. Investig. Dermatol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1085\/jgp.201711782","article-title":"The syndromic deafness mutation G12R impairs fast and slow gating in Cx26 hemichannels","volume":"150","author":"Villanelo","year":"2018","journal-title":"J. Gen. Physiol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1111\/exd.14187","article-title":"A heterozygous mutation in GJB2 (Cx26F142L) associated with deafness and recurrent skin rashes results in connexin assembly deficiencies","volume":"29","author":"Albuloushi","year":"2020","journal-title":"Exp. Dermatol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"416","DOI":"10.2353\/ajpath.2006.051242","article-title":"A novel N14Y mutation in Connexin26 in keratitis-ichthyosis-deafness syndrome: Analyses of altered gap junctional communication and molecular structure of N terminus of mutated Connexin26","volume":"169","author":"Arita","year":"2006","journal-title":"Am. J. Pathol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1111\/j.1600-0625.2010.01222.x","article-title":"Molecular analysis of connexin26 asparagine14 mutations associated with syndromic skin phenotypes","volume":"20","author":"Rosa","year":"2011","journal-title":"Exp. Dermatol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1085\/jgp.201611585","article-title":"Syndromic deafness mutations at Asn 14 differentially alter the open stability of Cx26 hemichannels","volume":"148","author":"Sanchez","year":"2016","journal-title":"J. Gen. Physiol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"9721","DOI":"10.1074\/jbc.M116.770917","article-title":"Induction of cell death and gain-of-function properties of connexin26 mutants predict severity of skin disorders and hearing loss","volume":"292","author":"Press","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1085\/jgp.201812219","article-title":"The connexin26 human mutation N14K disrupts cytosolic intersubunit interactions and promotes channel opening","volume":"151","author":"Chatterjee","year":"2019","journal-title":"J. Gen. Physiol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1002\/humu.9250","article-title":"GJB2 mutations in patients with non-syndromic hearing loss from Northeastern Hungary","volume":"23","author":"Kupka","year":"2004","journal-title":"Hum. Mutat."},{"key":"ref_103","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_104","doi-asserted-by":"crossref","first-page":"591","DOI":"10.2340\/00015555-1818","article-title":"Lethal form of keratitis-ichthyosis-deafness syndrome caused by the GJB2 mutation p.Ser17Phe","volume":"94","author":"Chiaverini","year":"2014","journal-title":"Acta Derm. Venereol."},{"key":"ref_105","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. (2023). 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_106","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_107","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_108","doi-asserted-by":"crossref","first-page":"59","DOI":"10.3109\/00016489.2010.506885","article-title":"Impaired membrane targeting and aberrant cellular localization of human Cx26 mutants associated with inherited recessive hearing loss","volume":"131","author":"Xiao","year":"2011","journal-title":"Acta Otolaryngol."},{"key":"ref_109","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_110","doi-asserted-by":"crossref","first-page":"2442","DOI":"10.1038\/s41436-019-0535-9","article-title":"Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel","volume":"21","author":"Shen","year":"2019","journal-title":"Genet. Med."},{"key":"ref_111","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_112","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_113","doi-asserted-by":"crossref","first-page":"2534","DOI":"10.1002\/ajmg.a.31982","article-title":"M34T and V37I mutations in GJB2 associated hearing impairment: Evidence for pathogenicity and reduced penetrance","volume":"143A","author":"Pollak","year":"2007","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1096\/fj.03-0763fje","article-title":"Aberrant gating, but a normal expression pattern, underlies the recessive phenotype of the deafness mutant Connexin26M34T","volume":"18","author":"Skerrett","year":"2004","journal-title":"FASEB J."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2569","DOI":"10.1093\/hmg\/ddl184","article-title":"Pathogenetic role of the deafness-related M34T mutation of Cx26","volume":"15","author":"Bicego","year":"2006","journal-title":"Hum. Mol. Genet."},{"key":"ref_116","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_117","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1007\/s00439-002-0750-2","article-title":"Human connexin26 (GJB2) deafness mutations affect the function of gap junction channels at different levels of protein expression","volume":"111","author":"Rabionet","year":"2002","journal-title":"Hum. Genet."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.nbd.2005.10.005","article-title":"Loss of function mutations of the GJB2 gene detected in patients with DFNB1-associated hearing impairment","volume":"22","author":"Palmada","year":"2006","journal-title":"Neurobiol. Dis."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1074\/jbc.M207713200","article-title":"Roles of Met-34, Cys-64, and Arg-75 in the assembly of human connexin 26. Implication for key amino acid residues for channel formation and function","volume":"278","author":"Oshima","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"85","DOI":"10.3389\/fphys.2014.00085","article-title":"Molecular dynamics simulations highlight structural and functional alterations in deafness-related M34T mutation of connexin 26","volume":"5","author":"Zonta","year":"2014","journal-title":"Front. Physiol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/S0014-5793(02)03755-9","article-title":"Loss-of-function and residual channel activity of connexin26 mutations associated with non-syndromic deafness","volume":"533","author":"Bruzzone","year":"2003","journal-title":"FEBS Lett."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"e169","DOI":"10.1038\/emm.2015.32","article-title":"Non-syndromic hearing loss caused by the dominant cis mutation R75Q with the recessive mutation V37I of the GJB2 (Connexin 26) gene","volume":"47","author":"Kim","year":"2015","journal-title":"Exp. Mol. Med."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.jaad.2003.12.042","article-title":"A novel connexin 26 gene mutation associated with features of the keratitis-ichthyosis-deafness syndrome and the follicular occlusion triad","volume":"51","author":"Montgomery","year":"2004","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"15201","DOI":"10.1073\/pnas.0501859102","article-title":"Gap junction-mediated intercellular biochemical coupling in cochlear supporting cells is required for normal cochlear functions","volume":"102","author":"Zhang","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"C337","DOI":"10.1152\/ajpcell.00626.2006","article-title":"Aberrant hemichannel properties of Cx26 mutations causing skin disease and deafness","volume":"293","author":"Gerido","year":"2007","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1085\/jgp.201010433","article-title":"Differentially altered Ca2+ regulation and Ca2+ permeability in Cx26 hemichannels formed by the A40V and G45E mutations that cause keratitis ichthyosis deafness syndrome","volume":"136","author":"Mese","year":"2010","journal-title":"J. Gen. Physiol."},{"key":"ref_127","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_128","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1016\/j.bbrc.2005.09.116","article-title":"Functional characterization of a novel Cx26 (T55N) mutation associated to non-syndromic hearing loss","volume":"337","author":"Melchionda","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1159\/000324004","article-title":"Functional analysis of a novel I71N mutation in the GJB2 gene among Southern Egyptians causing autosomal recessive hearing loss","volume":"26","author":"Mohamed","year":"2010","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"425","DOI":"10.3109\/15419060109080765","article-title":"Functional analysis of a dominant mutation of human connexin26 associated with nonsyndromic deafness","volume":"8","author":"Bruzzone","year":"2001","journal-title":"Cell Commun. Adhes."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1242\/jcs.114.11.2105","article-title":"Trans-dominant inhibition of connexin-43 by mutant connexin-26: Implications for dominant connexin disorders affecting epidermal differentiation","volume":"114","author":"Rouan","year":"2001","journal-title":"J. Cell Sci."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1093\/hmg\/ddg076","article-title":"Mutations in the gene for connexin 26 (GJB2) that cause hearing loss have a dominant negative effect on connexin 30","volume":"12","author":"Marziano","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.nbd.2010.01.010","article-title":"Dominant connexin26 mutants associated with human hearing loss have trans-dominant effects on connexin30","volume":"38","author":"Yum","year":"2010","journal-title":"Neurobiol. Dis."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.mcn.2010.10.002","article-title":"Dominant Cx26 mutants associated with hearing loss have dominant-negative effects on wild type Cx26","volume":"47","author":"Zhang","year":"2011","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"e2494","DOI":"10.7717\/peerj.2494","article-title":"Comparative functional characterization of novel non-syndromic GJB2 gene variant p.Gly45Arg and lethal syndromic variant p.Gly45Glu","volume":"4","author":"Waldhaus","year":"2016","journal-title":"PeerJ"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"E716","DOI":"10.1002\/humu.21036","article-title":"Different functional consequences of two missense mutations in the GJB2 gene associated with non-syndromic hearing loss","volume":"30","author":"Choi","year":"2009","journal-title":"Hum. Mutat."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1080\/cac.10.4-6.341.346","article-title":"The inner ear contains heteromeric channels composed of cx26 and cx30 and deafness-related mutations in cx26 have a dominant negative effect on cx30","volume":"10","author":"Forge","year":"2003","journal-title":"Cell Commun. Adhes."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"19157","DOI":"10.1074\/jbc.M314117200","article-title":"Functional domain mapping and selective trans-dominant effects exhibited by Cx26 disease-causing mutations","volume":"279","author":"Thomas","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_139","first-page":"161","article-title":"A novel missense mutation in GJB2 disturbs gap junction protein transport and causes focal palmoplantar keratoderma with deafness","volume":"45","author":"Hamm","year":"2008","journal-title":"J. Med. Genet."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/JID.2015.389","article-title":"Connexin26 Mutations Causing Palmoplantar Keratoderma and Deafness Interact with Connexin43, Modifying Gap Junction and Hemichannel Properties","volume":"136","author":"Shuja","year":"2016","journal-title":"J. Investig. Dermatol."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1046\/j.1365-2133.2002.04893.x","article-title":"HID and KID syndromes are associated with the same connexin 26 mutation","volume":"146","author":"Hennies","year":"2002","journal-title":"Br. J. Dermatol."},{"key":"ref_142","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_143","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1085\/jgp.201210893","article-title":"Insights on the mechanisms of Ca(2+) regulation of connexin26 hemichannels revealed by human pathogenic mutations (D50N\/Y)","volume":"142","author":"Lopez","year":"2013","journal-title":"J. Gen. Physiol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"C1150","DOI":"10.1152\/ajpcell.00374.2012","article-title":"The human Cx26-D50A and Cx26-A88V mutations causing keratitis-ichthyosis-deafness syndrome display increased hemichannel activity","volume":"304","author":"Mhaske","year":"2013","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1002\/ajmg.a.30515","article-title":"GJB2 mutations in keratitis-ichthyosis-deafness syndrome including its fatal form","volume":"133A","author":"Janecke","year":"2005","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/j.jaad.2018.09.042","article-title":"More than keratitis, ichthyosis, and deafness: Multisystem effects of lethal GJB2 mutations","volume":"80","author":"Lilly","year":"2019","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"4776","DOI":"10.1091\/mbc.e11-09-0778","article-title":"The Cx26-G45E mutation displays increased hemichannel activity in a mouse model of the lethal form of keratitis-ichthyosis-deafness syndrome","volume":"22","author":"Mese","year":"2011","journal-title":"Mol. Biol. Cell"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.bbrc.2013.05.118","article-title":"Conserved glycine at position 45 of major cochlear connexins constitutes a vital component of the Ca2+ sensor for gating of gap junction hemichannels","volume":"436","author":"Zhang","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_149","doi-asserted-by":"crossref","unstructured":"Ogawa, Y., Takeichi, T., Kono, M., Hamajima, N., Yamamoto, T., Sugiura, K., and Akiyama, M. (2014). Revertant mutation releases confined lethal mutation, opening Pandora\u2019s box: A novel genetic pathogenesis. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004276"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"1737","DOI":"10.1093\/hmg\/ddg183","article-title":"Targeted epidermal expression of mutant Connexin 26(D66H) mimics true Vohwinkel syndrome and provides a model for the pathogenesis of dominant connexin disorders","volume":"12","author":"Bakirtzis","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1111\/j.1365-2133.2010.10058.x","article-title":"A novel missense mutation in GJB2, p.Tyr65His, causes severe Vohwinkel syndrome","volume":"164","author":"Veysey","year":"2011","journal-title":"Br. J. Dermatol."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1007\/s004390050839","article-title":"Functional defects of Cx26 resulting from a heterozygous missense mutation in a family with dominant deaf-mutism and palmoplantar keratoderma","volume":"103","author":"Richard","year":"1998","journal-title":"Hum. Genet."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1080\/cac.10.4-6.353.358","article-title":"Transport and function of cx26 mutants involved in skin and deafness disorders","volume":"10","author":"Thomas","year":"2003","journal-title":"Cell Commun. Adhes."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1096\/fj.04-3491fje","article-title":"Mechanism of the defect in gap-junctional communication by expression of a connexin 26 mutant associated with dominant deafness","volume":"19","author":"Chen","year":"2005","journal-title":"FASEB J."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.heares.2006.07.004","article-title":"Mutations of connexin 26 at position 75 and dominant deafness: Essential role of arginine for the generation of functional gap-junctional channels","volume":"220","author":"Deng","year":"2006","journal-title":"Hear. Res."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1093\/hmg\/ddg116","article-title":"Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness","volume":"12","author":"Kudo","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.neures.2007.03.006","article-title":"Cochlear expression of a dominant-negative GJB2R75W construct delivered through the round window membrane in mice","volume":"58","author":"Maeda","year":"2007","journal-title":"Neurosci. Res."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1016\/j.neuroscience.2008.08.027","article-title":"Postnatal development of the organ of Corti in dominant-negative GJB2 transgenic mice","volume":"156","author":"Inoshita","year":"2008","journal-title":"Neuroscience"},{"key":"ref_159","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_160","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1002\/ajmg.a.30765","article-title":"The GJB2 mutation R75Q can cause nonsyndromic hearing loss DFNA3 or hereditary palmoplantar keratoderma with deafness","volume":"137","author":"Feldmann","year":"2005","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1111\/j.1399-0004.2005.00468.x","article-title":"Functional analysis of R75Q mutation in the gene coding for Connexin 26 identified in a family with nonsyndromic hearing loss","volume":"68","author":"Piazza","year":"2005","journal-title":"Clin. Genet."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"1798","DOI":"10.1002\/ajmg.a.33464","article-title":"Autosomal dominant prelingual hearing loss with palmoplantar keratoderma syndrome: Variability in clinical expression from mutations of R75W and R75Q in the GJB2 gene","volume":"152A","author":"Prera","year":"2010","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1046\/j.1471-4159.2003.01555.x","article-title":"Functional analysis of connexin-26 mutants associated with hereditary recessive deafness","volume":"84","author":"Wang","year":"2003","journal-title":"J. Neurochem."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1038\/ncb1205","article-title":"Impaired permeability to Ins(1,4,5)P3 in a mutant connexin underlies recessive hereditary deafness","volume":"7","author":"Beltramello","year":"2005","journal-title":"Nat. Cell Biol."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"310","DOI":"10.3892\/ijmm.2013.1581","article-title":"A novel compound heterozygous mutation in the GJB2 gene causing non-syndromic hearing loss in a family","volume":"33","author":"Wei","year":"2014","journal-title":"Int. J. Mol. Med."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"e22444","DOI":"10.1002\/jcla.22444","article-title":"A Novel GJB2 compound heterozygous mutation c.257C>G (p.T86R)\/c.176del16 (p.G59A fs*18) causes sensorineural hearing loss in a Chinese family","volume":"32","author":"Shi","year":"2018","journal-title":"J. Clin. Lab. Anal."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1002\/humu.9044","article-title":"Frequencies of GJB2 mutations in German control individuals and patients showing sporadic non-syndromic hearing impairment","volume":"20","author":"Kupka","year":"2002","journal-title":"Hum. Mutat."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1159\/000254487","article-title":"GJB2 and GJB6 genes: Molecular study and identification of novel GJB2 mutations in the hearing-impaired Argentinean population","volume":"15","author":"Lotersztein","year":"2010","journal-title":"Audiol. Neurootol."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1046\/j.1523-1747.2003.12550_4.x","article-title":"A novel GJB2 (connexin 26) mutation, F142L, in a patient with unusual mucocutaneous findings and deafness","volume":"121","author":"Brown","year":"2003","journal-title":"J. Investig. Dermatol."},{"key":"ref_170","first-page":"e138","article-title":"An unusual mucocutaneous syndrome with sensorineural deafness due to connexin 26 mutations","volume":"30","author":"Alcalde","year":"2013","journal-title":"Pediatr. Dermatol."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1111\/ahg.12062","article-title":"Update of the spectrum of GJB2 mutations in 107 patients with nonsyndromic hearing loss in the Fujian population of China","volume":"78","author":"Chen","year":"2014","journal-title":"Ann. Hum. Genet."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1038\/nm1202-1332","article-title":"Selection for deafness?","volume":"8","author":"Meyer","year":"2002","journal-title":"Nat. Med."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1136\/jmg.2003.017632","article-title":"Further evidence for heterozygote advantage of GJB2 deafness mutations: A link with cell survival","volume":"41","author":"Common","year":"2004","journal-title":"J. Med. Genet."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s00232-007-9025-0","article-title":"A deafness-associated mutant human connexin 26 improves the epithelial barrier in vitro","volume":"218","author":"Man","year":"2007","journal-title":"J. Membr. Biol."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.heares.2008.03.004","article-title":"A novel M163L mutation in connexin 26 causing cell death and associated with autosomal dominant hearing loss","volume":"240","author":"Matos","year":"2008","journal-title":"Hear. Res."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.2353\/ajpath.2008.080049","article-title":"A novel missense mutation in the second extracellular domain of GJB2, p.Ser183Phe, causes a syndrome of focal palmoplantar keratoderma with deafness","volume":"173","author":"Steijlen","year":"2008","journal-title":"Am. J. Pathol."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1038\/ejhg.2010.50","article-title":"Mutation R184Q of connexin 26 in hearing loss patients has a dominant-negative effect on connexin 26 and connexin 30","volume":"18","author":"Su","year":"2010","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1034\/j.1399-0004.2003.00079.x","article-title":"A novel dominant missense mutation--D179N--in the GJB2 gene (Connexin 26) associated with non-syndromic hearing loss","volume":"63","author":"Primignani","year":"2003","journal-title":"Clin. Genet."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1159\/000099024","article-title":"Identification of mutations in members of the connexin gene family as a cause of nonsyndromic deafness in Taiwan","volume":"12","author":"Yang","year":"2007","journal-title":"Audiol. Neurootol."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"2641","DOI":"10.1093\/hmg\/ddv026","article-title":"The p.Cys169Tyr variant of connexin 26 is not a polymorphism","volume":"24","author":"Zonta","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_181","doi-asserted-by":"crossref","unstructured":"Maslova, E.A., Orishchenko, K.E., and Posukh, O.L. (2021). Functional Evaluation of a Rare Variant c.516G>C (p.Trp172Cys) in the GJB2 (Connexin 26) Gene Associated with Nonsyndromic Hearing Loss. Biomolecules, 11.","DOI":"10.3390\/biom11010061"},{"key":"ref_182","doi-asserted-by":"crossref","unstructured":"Ambrosi, C., Walker, A.E., Depriest, A.D., Cone, A.C., Lu, C., Badger, J., Skerrett, I.M., and Sosinsky, G.E. (2013). Analysis of trafficking, stability and function of human connexin 26 gap junction channels with deafness-causing mutations in the fourth transmembrane helix. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0070916"},{"key":"ref_183","doi-asserted-by":"crossref","unstructured":"Birkenh\u00e4ger, R., Prera, N., Aschendorff, A., Laszig, R., and Arndt, S. (2014). A novel homozygous mutation in the EC1\/EC2 interaction domain of the gap junction complex connexon 26 leads to profound hearing impairment. Biomed. Res. Int., 2014.","DOI":"10.1155\/2014\/307976"},{"key":"ref_184","doi-asserted-by":"crossref","unstructured":"Posukh, O.L., Zytsar, M.V., Bady-Khoo, M.S., Danilchenko, V.Y., Maslova, E.A., Barashkov, N.A., Bondar, A.A., Morozov, I.V., Maximov, V.N., and Voevoda, M.I. (2019). Unique Mutational Spectrum of the GJB2 Gene and its Pathogenic Contribution to Deafness in Tuvinians (Southern Siberia, Russia): A High Prevalence of Rare Variant c.516G>C (p.Trp172Cys). Genes, 10.","DOI":"10.3390\/genes10060429"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/10\/1521\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:06:16Z","timestamp":1760130376000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/10\/1521"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,13]]},"references-count":184,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["biom13101521"],"URL":"https:\/\/doi.org\/10.3390\/biom13101521","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,13]]}}}