title: The pathological effects of connexin 26 variants related to hearing loss by in silico and in vitro analysis.
abstract: Gap junctions (GJs) are intercellular channels associated with cell-cell communication. Connexin 26 (Cx26) encoded by the GJB2 gene forms GJs of the inner ear, and mutations of GJB2 cause congenital hearing loss that can be syndromic or non-syndromic. It is difficult to predict pathogenic effects using only genetic analysis. Using ionic and biochemical coupling tests, we evaluated the pathogenic effects of Cx26 variants using computational analyses to predict structural abnormalities. For seven out of ten variants, we predicted the variation would result in a loss of GJ function, whereas the others would completely fail to form GJs. Functional studies demonstrated that, although all variants were able to function normally as hetero-oligomeric GJ channels, six variants (p.E47K, p.E47Q, p.H100L, p.H100Y, p.R127L, and p.M195L) did not function normally as homo-oligomeric GJ channels. Interestingly, GJs composed of the Cx26 variant p.R127H were able to function normally, even as homo-oligomeric GJ channels. This study demonstrates the particular location and property of an amino acid are more important mainly than the domain where they belong in the formation and function of GJ, and will provide information that is useful for the accurate diagnosis of hearing loss.
authors.affiliation: Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, 41566, South Korea.
authors.forename: Hui Ram
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, 41566, South Korea.|Division of Life Sciences, Korea Polar Research Institute (KOPRI), Incheon, 21990, South Korea.
authors.forename: Se-Kyung
authors.initials: SK
authors.lastname: Oh
authors.affiliation: Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, 41566, South Korea.
authors.forename: Eun-Shil
authors.initials: ES
authors.lastname: Lee
authors.affiliation: Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, 41566, South Korea.|Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Soo-Young
authors.initials: SY
authors.lastname: Choi
authors.affiliation: Department of Physiology, Seoul National University College of Medicine, Seoul, 08826, South Korea.
authors.forename: Seung-Eon
authors.initials: SE
authors.lastname: Roh
authors.affiliation: Department of Physiology, Seoul National University College of Medicine, Seoul, 08826, South Korea.
authors.forename: Sang Jeong
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Institute for Protein Research, Osaka University, 3-2, Yamada-oka, Suita, Osaka, 565-0871, Japan.|Picobiology Institute, Graduate School of Life Science, University of Hyogo, Kamigohori, Akoh, Hyogo, 678-1297, Japan.
authors.forename: Tomitake
authors.initials: T
authors.lastname: Tsukihara
authors.affiliation: Department of Otolaryngology, College of Medicine, Kyungpook National University, Daegu, 41944, South Korea.
authors.forename: Kyu-Yup
authors.initials: KY
authors.lastname: Lee
authors.affiliation: Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, 41566, South Korea. cjjeon@knu.ac.kr.|School of Life Sciences, BrainKorea21 PLUS KNU Creative BioResearch Group, Kyungpook National University, Daegu, 41566, South Korea. cjjeon@knu.ac.kr.
authors.forename: Chang-Jin
authors.initials: CJ
authors.lastname: Jeon
authors.affiliation: Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, 41566, South Korea. kimuk@knu.ac.kr.|School of Life Sciences, BrainKorea21 PLUS KNU Creative BioResearch Group, Kyungpook National University, Daegu, 41566, South Korea. kimuk@knu.ac.kr.
authors.forename: Un-Kyung
authors.initials: UK
authors.lastname: Kim
mesh_terms: D003001:Cloning, Molecular; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D017629:Gap Junctions / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006367:HeLa Cells; D034381:Hearing Loss / Q000235:genetics* / Q000473:pathology; D006801:Humans; D009154:Mutation; D011487:Protein Conformation; D014162:Transfection
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26