Cingulin regulates hair cell cuticular plate morphology and is required for hearing in human and mouse
Abstract 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 repor...
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| Language: | English |
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Springer Nature
2023-09-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202317611 |
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| author | Guang‐Jie Zhu Yuhang Huang Linqing Zhang Keji Yan Cui Qiu Yihan He Qing Liu Chengwen Zhu Matías Morín Miguel Ángel Moreno‐Pelayo Min‐Sheng Zhu Xin Cao Han Zhou Xiaoyun Qian Zhigang Xu Jie Chen Xia Gao Guoqiang Wan |
| author_facet | Guang‐Jie Zhu Yuhang Huang Linqing Zhang Keji Yan Cui Qiu Yihan He Qing Liu Chengwen Zhu Matías Morín Miguel Ángel Moreno‐Pelayo Min‐Sheng Zhu Xin Cao Han Zhou Xiaoyun Qian Zhigang Xu Jie Chen Xia Gao Guoqiang Wan |
| author_sort | Guang‐Jie Zhu |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-8e775ad618694efebba7ec761a5f62d4 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2023-09-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-8e775ad618694efebba7ec761a5f62d42025-08-20T03:43:25ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-09-01151112010.15252/emmm.202317611Cingulin regulates hair cell cuticular plate morphology and is required for hearing in human and mouseGuang‐Jie Zhu0Yuhang Huang1Linqing Zhang2Keji Yan3Cui Qiu4Yihan He5Qing Liu6Chengwen Zhu7Matías Morín8Miguel Ángel Moreno‐Pelayo9Min‐Sheng Zhu10Xin Cao11Han Zhou12Xiaoyun Qian13Zhigang Xu14Jie Chen15Xia Gao16Guoqiang Wan17State 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 UniversityState 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 UniversityState 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 UniversityShandong 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 UniversityState 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 UniversityState 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 UniversityState 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 UniversityState 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 UniversityServicio de Genética, Hospital Universitario Ramón y Cajal, IRYCISServicio de Genética, Hospital Universitario Ramón y Cajal, IRYCISState 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 UniversityDepartment of Medical Genetics, School of Basic Medical Science, Nanjing Medical UniversityState 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 UniversityState 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 UniversityShandong 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 UniversityState 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 UniversityState 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 UniversityState 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 UniversityAbstract 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.https://doi.org/10.15252/emmm.202317611ADNSHLcingulincuticular platehair cellshearing loss |
| spellingShingle | Guang‐Jie Zhu Yuhang Huang Linqing Zhang Keji Yan Cui Qiu Yihan He Qing Liu Chengwen Zhu Matías Morín Miguel Ángel Moreno‐Pelayo Min‐Sheng Zhu Xin Cao Han Zhou Xiaoyun Qian Zhigang Xu Jie Chen Xia Gao Guoqiang Wan Cingulin regulates hair cell cuticular plate morphology and is required for hearing in human and mouse EMBO Molecular Medicine ADNSHL cingulin cuticular plate hair cells hearing loss |
| title | Cingulin regulates hair cell cuticular plate morphology and is required for hearing in human and mouse |
| title_full | Cingulin regulates hair cell cuticular plate morphology and is required for hearing in human and mouse |
| title_fullStr | Cingulin regulates hair cell cuticular plate morphology and is required for hearing in human and mouse |
| title_full_unstemmed | Cingulin regulates hair cell cuticular plate morphology and is required for hearing in human and mouse |
| title_short | Cingulin regulates hair cell cuticular plate morphology and is required for hearing in human and mouse |
| title_sort | cingulin regulates hair cell cuticular plate morphology and is required for hearing in human and mouse |
| topic | ADNSHL cingulin cuticular plate hair cells hearing loss |
| url | https://doi.org/10.15252/emmm.202317611 |
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