Modeling of auditory neuropathy spectrum disorders associated with the TEME43 variant reveals impaired gap junction function of iPSC-derived glia-like support cells
Auditory neuropathy spectrum disorder (ANSD) is an auditory dysfunction disorder characterized by impaired speech comprehension. Its etiology is complex and can be broadly categorized into genetic and non-genetic factors. TMEM43 mutation is identified as a causative factor in ANSD. While some studie...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2024.1457874/full |
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| author | Xiaoming Kang Xiaoming Kang Lu Ma Lu Ma Lu Ma Jie Wen Jie Wen Wei Gong Wei Gong Xianlin Liu Xianlin Liu Yihan Hu Yihan Hu Zhili Feng Zhili Feng Qiancheng Jing Qiancheng Jing Yuexiang Cai Yuexiang Cai Sijun Li Xinzhang Cai Kai Yuan Yong Feng Yong Feng Yong Feng Yong Feng Yong Feng |
| author_facet | Xiaoming Kang Xiaoming Kang Lu Ma Lu Ma Lu Ma Jie Wen Jie Wen Wei Gong Wei Gong Xianlin Liu Xianlin Liu Yihan Hu Yihan Hu Zhili Feng Zhili Feng Qiancheng Jing Qiancheng Jing Yuexiang Cai Yuexiang Cai Sijun Li Xinzhang Cai Kai Yuan Yong Feng Yong Feng Yong Feng Yong Feng Yong Feng |
| author_sort | Xiaoming Kang |
| collection | DOAJ |
| description | Auditory neuropathy spectrum disorder (ANSD) is an auditory dysfunction disorder characterized by impaired speech comprehension. Its etiology is complex and can be broadly categorized into genetic and non-genetic factors. TMEM43 mutation is identified as a causative factor in ANSD. While some studies have been conducted using animal models, its pathogenic mechanisms in humans remain unclear. TMEM43 is predominantly expressed in cochlear glia-like support cells (GLSs) and plays a vital role in gap junction intercellular communication. In this work, we utilized induced pluripotent stem cells from an ANSD patient carrying the TMEM43 gene mutation c.1114C>T (p.Arg372Ter) and directed their differentiation toward GLSs to investigate the effect of TMEM43 mutation on the function of gap junctions in cochlear GLSs in vitro. Reduced expression of genes associated with GLSs characteristics and reduced gap junction intercellular communication in TMEM43 mutant cell lines were observed compared to controls. Transcriptome analysis revealed that differentially expressed genes were significantly enriched in pathways related to cell proliferation, differentiation, extracellular space and adhesion. Furthermore, significant alterations were noted in the PI3K-Akt signaling pathway and the calcium signaling pathway, which could potentially influence gap junction function and contribute to hearing loss. In summary, our study based on patient-derived iPSCs sheds new light on the molecular mechanisms by which TMEM43 mutations may lead to ANSD. These mutations could result in developmental defects in GLSs and a diminished capacity for gap junction function, which may be implicated in the auditory deficits observed in ANSD patients. Our study explored the pathological effects of the TMEM43 mutation and its causal relationship with ANSD using a patient-derived iPSC-based GLSs model, providing a foundation for future mechanistic studies and potential drug screening efforts. |
| format | Article |
| id | doaj-art-8a047cb39eb84b90a343334466413373 |
| institution | Kabale University |
| issn | 1662-5099 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj-art-8a047cb39eb84b90a3433344664133732025-01-06T06:59:42ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992025-01-011710.3389/fnmol.2024.14578741457874Modeling of auditory neuropathy spectrum disorders associated with the TEME43 variant reveals impaired gap junction function of iPSC-derived glia-like support cellsXiaoming Kang0Xiaoming Kang1Lu Ma2Lu Ma3Lu Ma4Jie Wen5Jie Wen6Wei Gong7Wei Gong8Xianlin Liu9Xianlin Liu10Yihan Hu11Yihan Hu12Zhili Feng13Zhili Feng14Qiancheng Jing15Qiancheng Jing16Yuexiang Cai17Yuexiang Cai18Sijun Li19Xinzhang Cai20Kai Yuan21Yong Feng22Yong Feng23Yong Feng24Yong Feng25Yong Feng26Department of Otorhinolaryngology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, ChinaInstitute of Otorhinolaryngology, Head and Neck Surgery, University of South China, Changsha, ChinaInstitute of Otorhinolaryngology, Head and Neck Surgery, University of South China, Changsha, ChinaMOE Key Lab of Rare Pediatric Diseases & Institute for Future Sciences, University of South China, Changsha, ChinaInstitute of Cytology and Genetics, Hengyang Medical School, University of South China, Hengyang, ChinaDepartment of Otorhinolaryngology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, ChinaInstitute of Otorhinolaryngology, Head and Neck Surgery, University of South China, Changsha, ChinaDepartment of Otorhinolaryngology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, ChinaInstitute of Otorhinolaryngology, Head and Neck Surgery, University of South China, Changsha, ChinaDepartment of Otorhinolaryngology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, ChinaInstitute of Otorhinolaryngology, Head and Neck Surgery, University of South China, Changsha, ChinaDepartment of Otorhinolaryngology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, ChinaInstitute of Otorhinolaryngology, Head and Neck Surgery, University of South China, Changsha, ChinaDepartment of Otorhinolaryngology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, ChinaInstitute of Otorhinolaryngology, Head and Neck Surgery, University of South China, Changsha, ChinaDepartment of Otorhinolaryngology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, ChinaInstitute of Otorhinolaryngology, Head and Neck Surgery, University of South China, Changsha, ChinaDepartment of Otorhinolaryngology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, ChinaInstitute of Otorhinolaryngology, Head and Neck Surgery, University of South China, Changsha, ChinaDepartment of Otorhinolaryngology, Xiangya Hospital Central South University, Changsha, ChinaDepartment of Otorhinolaryngology, Xiangya Hospital Central South University, Changsha, ChinaHunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, ChinaDepartment of Otorhinolaryngology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, ChinaInstitute of Otorhinolaryngology, Head and Neck Surgery, University of South China, Changsha, ChinaMOE Key Lab of Rare Pediatric Diseases & Institute for Future Sciences, University of South China, Changsha, ChinaInstitute of Cytology and Genetics, Hengyang Medical School, University of South China, Hengyang, ChinaDepartment of Otorhinolaryngology, Xiangya Hospital Central South University, Changsha, ChinaAuditory neuropathy spectrum disorder (ANSD) is an auditory dysfunction disorder characterized by impaired speech comprehension. Its etiology is complex and can be broadly categorized into genetic and non-genetic factors. TMEM43 mutation is identified as a causative factor in ANSD. While some studies have been conducted using animal models, its pathogenic mechanisms in humans remain unclear. TMEM43 is predominantly expressed in cochlear glia-like support cells (GLSs) and plays a vital role in gap junction intercellular communication. In this work, we utilized induced pluripotent stem cells from an ANSD patient carrying the TMEM43 gene mutation c.1114C>T (p.Arg372Ter) and directed their differentiation toward GLSs to investigate the effect of TMEM43 mutation on the function of gap junctions in cochlear GLSs in vitro. Reduced expression of genes associated with GLSs characteristics and reduced gap junction intercellular communication in TMEM43 mutant cell lines were observed compared to controls. Transcriptome analysis revealed that differentially expressed genes were significantly enriched in pathways related to cell proliferation, differentiation, extracellular space and adhesion. Furthermore, significant alterations were noted in the PI3K-Akt signaling pathway and the calcium signaling pathway, which could potentially influence gap junction function and contribute to hearing loss. In summary, our study based on patient-derived iPSCs sheds new light on the molecular mechanisms by which TMEM43 mutations may lead to ANSD. These mutations could result in developmental defects in GLSs and a diminished capacity for gap junction function, which may be implicated in the auditory deficits observed in ANSD patients. Our study explored the pathological effects of the TMEM43 mutation and its causal relationship with ANSD using a patient-derived iPSC-based GLSs model, providing a foundation for future mechanistic studies and potential drug screening efforts.https://www.frontiersin.org/articles/10.3389/fnmol.2024.1457874/fullauditory neuropathy spectrum disorderTMEM43glia-like support cellsgap junctioninduced pluripotent stem cellsRNA-Seq |
| spellingShingle | Xiaoming Kang Xiaoming Kang Lu Ma Lu Ma Lu Ma Jie Wen Jie Wen Wei Gong Wei Gong Xianlin Liu Xianlin Liu Yihan Hu Yihan Hu Zhili Feng Zhili Feng Qiancheng Jing Qiancheng Jing Yuexiang Cai Yuexiang Cai Sijun Li Xinzhang Cai Kai Yuan Yong Feng Yong Feng Yong Feng Yong Feng Yong Feng Modeling of auditory neuropathy spectrum disorders associated with the TEME43 variant reveals impaired gap junction function of iPSC-derived glia-like support cells Frontiers in Molecular Neuroscience auditory neuropathy spectrum disorder TMEM43 glia-like support cells gap junction induced pluripotent stem cells RNA-Seq |
| title | Modeling of auditory neuropathy spectrum disorders associated with the TEME43 variant reveals impaired gap junction function of iPSC-derived glia-like support cells |
| title_full | Modeling of auditory neuropathy spectrum disorders associated with the TEME43 variant reveals impaired gap junction function of iPSC-derived glia-like support cells |
| title_fullStr | Modeling of auditory neuropathy spectrum disorders associated with the TEME43 variant reveals impaired gap junction function of iPSC-derived glia-like support cells |
| title_full_unstemmed | Modeling of auditory neuropathy spectrum disorders associated with the TEME43 variant reveals impaired gap junction function of iPSC-derived glia-like support cells |
| title_short | Modeling of auditory neuropathy spectrum disorders associated with the TEME43 variant reveals impaired gap junction function of iPSC-derived glia-like support cells |
| title_sort | modeling of auditory neuropathy spectrum disorders associated with the teme43 variant reveals impaired gap junction function of ipsc derived glia like support cells |
| topic | auditory neuropathy spectrum disorder TMEM43 glia-like support cells gap junction induced pluripotent stem cells RNA-Seq |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2024.1457874/full |
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