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The pathogenesis of common Gjb2 mutations associated with human hereditary deafness in mice

Mutations in GJB2 (Gap junction protein beta 2) are the most common genetic cause of non-syndromic hereditary deafness in humans, especially the 35delG and 235delC mutations. Owing to the homozygous lethality of Gjb2 mutations in mice, there are currently no perfect mouse models carrying Gjb2 mutati...

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Autores principales: Li, Qing, Cui, Chong, Liao, Rongyu, Yin, Xidi, Wang, Daqi, Cheng, Yanbo, Huang, Bowei, Wang, Liqin, Yan, Meng, Zhou, Jinan, Zhao, Jingjing, Tang, Wei, Wang, Yingyi, Wang, Xiaohan, Lv, Jun, Li, Jinsong, Li, Huawei, Shu, Yilai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10182940/
https://www.ncbi.nlm.nih.gov/pubmed/37178259
http://dx.doi.org/10.1007/s00018-023-04794-9
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author Li, Qing
Cui, Chong
Liao, Rongyu
Yin, Xidi
Wang, Daqi
Cheng, Yanbo
Huang, Bowei
Wang, Liqin
Yan, Meng
Zhou, Jinan
Zhao, Jingjing
Tang, Wei
Wang, Yingyi
Wang, Xiaohan
Lv, Jun
Li, Jinsong
Li, Huawei
Shu, Yilai
author_facet Li, Qing
Cui, Chong
Liao, Rongyu
Yin, Xidi
Wang, Daqi
Cheng, Yanbo
Huang, Bowei
Wang, Liqin
Yan, Meng
Zhou, Jinan
Zhao, Jingjing
Tang, Wei
Wang, Yingyi
Wang, Xiaohan
Lv, Jun
Li, Jinsong
Li, Huawei
Shu, Yilai
author_sort Li, Qing
collection PubMed
description Mutations in GJB2 (Gap junction protein beta 2) are the most common genetic cause of non-syndromic hereditary deafness in humans, especially the 35delG and 235delC mutations. Owing to the homozygous lethality of Gjb2 mutations in mice, there are currently no perfect mouse models carrying Gjb2 mutations derived from patients for mimicking human hereditary deafness and for unveiling the pathogenesis of the disease. Here, we successfully constructed heterozygous Gjb2(+/35delG) and Gjb2(+/235delC) mutant mice through advanced androgenic haploid embryonic stem cell (AG-haESC)-mediated semi-cloning technology, and these mice showed normal hearing at postnatal day (P) 28. A homozygous mutant mouse model, Gjb2(35delG/35delG), was then generated using enhanced tetraploid embryo complementation, demonstrating that GJB2 plays an indispensable role in mouse placenta development. These mice exhibited profound hearing loss similar to human patients at P14, i.e., soon after the onset of hearing. Mechanistic analyses showed that Gjb2 35delG disrupts the function and formation of intercellular gap junction channels of the cochlea rather than affecting the survival and function of hair cells. Collectively, our study provides ideal mouse models for understanding the pathogenic mechanism of DFNB1A-related hereditary deafness and opens up a new avenue for investigating the treatment of this disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-023-04794-9.
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spelling pubmed-101829402023-05-15 The pathogenesis of common Gjb2 mutations associated with human hereditary deafness in mice Li, Qing Cui, Chong Liao, Rongyu Yin, Xidi Wang, Daqi Cheng, Yanbo Huang, Bowei Wang, Liqin Yan, Meng Zhou, Jinan Zhao, Jingjing Tang, Wei Wang, Yingyi Wang, Xiaohan Lv, Jun Li, Jinsong Li, Huawei Shu, Yilai Cell Mol Life Sci Original Article Mutations in GJB2 (Gap junction protein beta 2) are the most common genetic cause of non-syndromic hereditary deafness in humans, especially the 35delG and 235delC mutations. Owing to the homozygous lethality of Gjb2 mutations in mice, there are currently no perfect mouse models carrying Gjb2 mutations derived from patients for mimicking human hereditary deafness and for unveiling the pathogenesis of the disease. Here, we successfully constructed heterozygous Gjb2(+/35delG) and Gjb2(+/235delC) mutant mice through advanced androgenic haploid embryonic stem cell (AG-haESC)-mediated semi-cloning technology, and these mice showed normal hearing at postnatal day (P) 28. A homozygous mutant mouse model, Gjb2(35delG/35delG), was then generated using enhanced tetraploid embryo complementation, demonstrating that GJB2 plays an indispensable role in mouse placenta development. These mice exhibited profound hearing loss similar to human patients at P14, i.e., soon after the onset of hearing. Mechanistic analyses showed that Gjb2 35delG disrupts the function and formation of intercellular gap junction channels of the cochlea rather than affecting the survival and function of hair cells. Collectively, our study provides ideal mouse models for understanding the pathogenic mechanism of DFNB1A-related hereditary deafness and opens up a new avenue for investigating the treatment of this disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-023-04794-9. Springer International Publishing 2023-05-13 2023 /pmc/articles/PMC10182940/ /pubmed/37178259 http://dx.doi.org/10.1007/s00018-023-04794-9 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Article
Li, Qing
Cui, Chong
Liao, Rongyu
Yin, Xidi
Wang, Daqi
Cheng, Yanbo
Huang, Bowei
Wang, Liqin
Yan, Meng
Zhou, Jinan
Zhao, Jingjing
Tang, Wei
Wang, Yingyi
Wang, Xiaohan
Lv, Jun
Li, Jinsong
Li, Huawei
Shu, Yilai
The pathogenesis of common Gjb2 mutations associated with human hereditary deafness in mice
title The pathogenesis of common Gjb2 mutations associated with human hereditary deafness in mice
title_full The pathogenesis of common Gjb2 mutations associated with human hereditary deafness in mice
title_fullStr The pathogenesis of common Gjb2 mutations associated with human hereditary deafness in mice
title_full_unstemmed The pathogenesis of common Gjb2 mutations associated with human hereditary deafness in mice
title_short The pathogenesis of common Gjb2 mutations associated with human hereditary deafness in mice
title_sort pathogenesis of common gjb2 mutations associated with human hereditary deafness in mice
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10182940/
https://www.ncbi.nlm.nih.gov/pubmed/37178259
http://dx.doi.org/10.1007/s00018-023-04794-9
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