Cingulin regulates hair cell cuticular plate morphology and is required for hearing in human and mouse.

Autor:	Zhu GJ; State Key Laboratory of Pharmaceutical Biotechnology, Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), The Affiliated Drum Tower Hospital of Medical School, Model Animal Research Center of Medical School, Nanjing University, Nanjing, China.; MOE Key Laboratory of Model Animal for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, National Resource Center for Mutant Mice of China, Nanjing University, Nanjing, China.; Research Institute of Otolaryngology, Nanjing, China., Huang Y; State Key Laboratory of Pharmaceutical Biotechnology, Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), The Affiliated Drum Tower Hospital of Medical School, Model Animal Research Center of Medical School, Nanjing University, Nanjing, China.; MOE Key Laboratory of Model Animal for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, National Resource Center for Mutant Mice of China, Nanjing University, Nanjing, China., Zhang L; State Key Laboratory of Pharmaceutical Biotechnology, Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), The Affiliated Drum Tower Hospital of Medical School, Model Animal Research Center of Medical School, Nanjing University, Nanjing, China.; MOE Key Laboratory of Model Animal for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, National Resource Center for Mutant Mice of China, Nanjing University, Nanjing, China., Yan K; Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology and Key Laboratory for Experimental Teratology of the Ministry of Education, School of Life Sciences, Shandong University, Qingdao, China., Qiu C; State Key Laboratory of Pharmaceutical Biotechnology, Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), The Affiliated Drum Tower Hospital of Medical School, Model Animal Research Center of Medical School, Nanjing University, Nanjing, China.; MOE Key Laboratory of Model Animal for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, National Resource Center for Mutant Mice of China, Nanjing University, Nanjing, China., He Y; State Key Laboratory of Pharmaceutical Biotechnology, Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), The Affiliated Drum Tower Hospital of Medical School, Model Animal Research Center of Medical School, Nanjing University, Nanjing, China.; MOE Key Laboratory of Model Animal for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, National Resource Center for Mutant Mice of China, Nanjing University, Nanjing, China., Liu Q; State Key Laboratory of Pharmaceutical Biotechnology, Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), The Affiliated Drum Tower Hospital of Medical School, Model Animal Research Center of Medical School, Nanjing University, Nanjing, China.; MOE Key Laboratory of Model Animal for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, National Resource Center for Mutant Mice of China, Nanjing University, Nanjing, China.; Research Institute of Otolaryngology, Nanjing, China., Zhu C; State Key Laboratory of Pharmaceutical Biotechnology, Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), The Affiliated Drum Tower Hospital of Medical School, Model Animal Research Center of Medical School, Nanjing University, Nanjing, China.; MOE Key Laboratory of Model Animal for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, National Resource Center for Mutant Mice of China, Nanjing University, Nanjing, China.; Research Institute of Otolaryngology, Nanjing, China., Morín M; Servicio de Genética, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III (CB06/07/0048; CIBERER-ISCIII), Madrid, Spain., Moreno-Pelayo MÁ; Servicio de Genética, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III (CB06/07/0048; CIBERER-ISCIII), Madrid, Spain., Zhu MS; State Key Laboratory of Pharmaceutical Biotechnology, Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), The Affiliated Drum Tower Hospital of Medical School, Model Animal Research Center of Medical School, Nanjing University, Nanjing, China.; MOE Key Laboratory of Model Animal for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, National Resource Center for Mutant Mice of China, Nanjing University, Nanjing, China.; Research Institute of Otolaryngology, Nanjing, China., Cao X; Department of Medical Genetics, School of Basic Medical Science, Nanjing Medical University, Nanjing, China., Zhou H; State Key Laboratory of Pharmaceutical Biotechnology, Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), The Affiliated Drum Tower Hospital of Medical School, Model Animal Research Center of Medical School, Nanjing University, Nanjing, China.; Research Institute of Otolaryngology, Nanjing, China., Qian X; State Key Laboratory of Pharmaceutical Biotechnology, Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), The Affiliated Drum Tower Hospital of Medical School, Model Animal Research Center of Medical School, Nanjing University, Nanjing, China.; Research Institute of Otolaryngology, Nanjing, China., Xu Z; Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology and Key Laboratory for Experimental Teratology of the Ministry of Education, School of Life Sciences, Shandong University, Qingdao, China., Chen J; State Key Laboratory of Pharmaceutical Biotechnology, Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), The Affiliated Drum Tower Hospital of Medical School, Model Animal Research Center of Medical School, Nanjing University, Nanjing, China.; Research Institute of Otolaryngology, Nanjing, China., Gao X; State Key Laboratory of Pharmaceutical Biotechnology, Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), The Affiliated Drum Tower Hospital of Medical School, Model Animal Research Center of Medical School, Nanjing University, Nanjing, China.; Research Institute of Otolaryngology, Nanjing, China., Wan G; State Key Laboratory of Pharmaceutical Biotechnology, Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), The Affiliated Drum Tower Hospital of Medical School, Model Animal Research Center of Medical School, Nanjing University, Nanjing, China.; MOE Key Laboratory of Model Animal for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, National Resource Center for Mutant Mice of China, Nanjing University, Nanjing, China.; Research Institute of Otolaryngology, Nanjing, China.
Jazyk:	angličtina
Zdroj:	EMBO molecular medicine [EMBO Mol Med] 2023 Nov 08; Vol. 15 (11), pp. e17611. Date of Electronic Publication: 2023 Sep 11.
DOI:	10.15252/emmm.202317611
Abstrakt:	Cingulin (CGN) is a cytoskeleton-associated protein localized at the apical junctions of epithelial cells. CGN interacts with major cytoskeletal filaments and regulates RhoA activity. However, physiological roles of CGN in development and human diseases are currently unknown. Here, we report a multi-generation family presenting with autosomal dominant non-syndromic hearing loss (ADNSHL) that co-segregates with a CGN heterozygous truncating variant, c.3330delG (p.Leu1110Leufs*17). CGN is normally expressed at the apical cell junctions of the organ of Corti, with enriched localization at hair cell cuticular plates and circumferential belts. In mice, the putative disease-causing mutation results in reduced expression and abnormal subcellular localization of the CGN protein, abolishes its actin polymerization activity, and impairs the normal morphology of hair cell cuticular plates and hair bundles. Hair cell-specific Cgn knockout leads to high-frequency hearing loss. Importantly, Cgn mutation knockin mice display noise-sensitive, progressive hearing loss and outer hair cell degeneration. In summary, we identify CGN c.3330delG as a pathogenic variant for ADNSHL and reveal essential roles of CGN in the maintenance of cochlear hair cell structures and auditory function. (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze:	MEDLINE
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