A novel BCAP31 variant associated with nonsyndromic auditory neuropathy spectrum disorder: mitochondrial dysfunction, cisplatin sensitivity, and amenability to mitochondrial transplantation
Abstract Background A novel in-frame insertion variant in the B-Cell Receptor-Associated Protein 31 (BCAP31) gene, which encodes a crucial ER membrane protein involved in the quality control and transport of transmembrane proteins, as well as in ER-mitochondria apoptotic signaling, was determined in...
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BMC
2025-06-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06610-3 |
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| author | Yehree Kim Yujin Kim Bong Jik Kim Shin-Hye Yu Jin Hee Han Minyoung Kim Nayoung Yi Seo-Eun Lee Ju Ang Kim Kyuboem Han Chun-Hyung Kim Young Cheol Kang Byung Yoon Choi |
| author_facet | Yehree Kim Yujin Kim Bong Jik Kim Shin-Hye Yu Jin Hee Han Minyoung Kim Nayoung Yi Seo-Eun Lee Ju Ang Kim Kyuboem Han Chun-Hyung Kim Young Cheol Kang Byung Yoon Choi |
| author_sort | Yehree Kim |
| collection | DOAJ |
| description | Abstract Background A novel in-frame insertion variant in the B-Cell Receptor-Associated Protein 31 (BCAP31) gene, which encodes a crucial ER membrane protein involved in the quality control and transport of transmembrane proteins, as well as in ER-mitochondria apoptotic signaling, was determined in a family demonstrating X-linked, recessive, nonsyndromic auditory neuropathy spectrum disorder (ANSD). Methods Exome sequencing analysiswas followed by bioinformatics analysis to identify the cause of hearing loss in a family whose pedigree indicated an X-linked recessive mode of inheritance. Immunohistochemistry was performed to locate Bcap31 in the mouse cochlea. Mitochondrial function was evaluated by measuring intracellular ATP, ROS and mitochondrial membrane potential in control and patient-derived lymphoblastoid cells (LCLs) before and after the administration of mitochondria isolated from human umbilical cord mesenchymal stem cells (UC-MSCs). Results ANSD observed in our study is characterized by initial inner hair cell damage, followed by accelerated degeneration of cochlear outer hair cells. Functional studies of patient-derived LCLs revealed mitochondrial dysfunction, evidenced by increased ROS, reduced ATP levels, and decreased mitochondrial membrane potential compared with normal LCLs. Further, these cells demonstrated heightened sensitivity to cisplatin-induced apoptosis, as indicated by the increased proapoptotic gene expression. Notably, the administration of mitochondria isolated from umbilical cord mesenchymal stem cells significantly restored mitochondrial dysfunction and alleviated cisplatin-induced cytotoxicity in the patient-derived cells. Conclusions These results indicate BCAP31 dysfunction as a potential cause of transient ANSD, progressing to sensorineural hearing loss through mitochondrial impairment. Furthermore, they highlighted the therapeutic potential of allogenic mitochondrial transplantation as a novel strategy for treating hearing loss with an underlying component of mitochondrial dysfunction. This study contributes to the understanding of BCAP31’s role in auditory neuropathy and mitochondrial health. Graphical Abstract |
| format | Article |
| id | doaj-art-c69c6bd787f9418280cf2b59e0af917f |
| institution | OA Journals |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-c69c6bd787f9418280cf2b59e0af917f2025-08-20T02:05:14ZengBMCJournal of Translational Medicine1479-58762025-06-0123111510.1186/s12967-025-06610-3A novel BCAP31 variant associated with nonsyndromic auditory neuropathy spectrum disorder: mitochondrial dysfunction, cisplatin sensitivity, and amenability to mitochondrial transplantationYehree Kim0Yujin Kim1Bong Jik Kim2Shin-Hye Yu3Jin Hee Han4Minyoung Kim5Nayoung Yi6Seo-Eun Lee7Ju Ang Kim8Kyuboem Han9Chun-Hyung Kim10Young Cheol Kang11Byung Yoon Choi12Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University College of Medicine, Seoul National University Bundang HospitalPaean BiotechnologyDepartment of Otolaryngology—Head and Neck Surgery, Chungnam National University College of Medicine, Chungnam National University Sejong HospitalPaean BiotechnologyDepartment of Otorhinolaryngology-Head and Neck Surgery, Seoul National University College of Medicine, Seoul National University Bundang HospitalDepartment of Otorhinolaryngology-Head and Neck Surgery, Seoul National University College of Medicine, Seoul National University Bundang HospitalDepartment of Otorhinolaryngology-Head and Neck Surgery, Seoul National University College of Medicine, Seoul National University Bundang HospitalPaean BiotechnologyDepartment of Otorhinolaryngology-Head and Neck Surgery, Seoul National University College of Medicine, Seoul National University Bundang HospitalPaean BiotechnologyPaean BiotechnologyPaean BiotechnologyDepartment of Otorhinolaryngology-Head and Neck Surgery, Seoul National University College of Medicine, Seoul National University Bundang HospitalAbstract Background A novel in-frame insertion variant in the B-Cell Receptor-Associated Protein 31 (BCAP31) gene, which encodes a crucial ER membrane protein involved in the quality control and transport of transmembrane proteins, as well as in ER-mitochondria apoptotic signaling, was determined in a family demonstrating X-linked, recessive, nonsyndromic auditory neuropathy spectrum disorder (ANSD). Methods Exome sequencing analysiswas followed by bioinformatics analysis to identify the cause of hearing loss in a family whose pedigree indicated an X-linked recessive mode of inheritance. Immunohistochemistry was performed to locate Bcap31 in the mouse cochlea. Mitochondrial function was evaluated by measuring intracellular ATP, ROS and mitochondrial membrane potential in control and patient-derived lymphoblastoid cells (LCLs) before and after the administration of mitochondria isolated from human umbilical cord mesenchymal stem cells (UC-MSCs). Results ANSD observed in our study is characterized by initial inner hair cell damage, followed by accelerated degeneration of cochlear outer hair cells. Functional studies of patient-derived LCLs revealed mitochondrial dysfunction, evidenced by increased ROS, reduced ATP levels, and decreased mitochondrial membrane potential compared with normal LCLs. Further, these cells demonstrated heightened sensitivity to cisplatin-induced apoptosis, as indicated by the increased proapoptotic gene expression. Notably, the administration of mitochondria isolated from umbilical cord mesenchymal stem cells significantly restored mitochondrial dysfunction and alleviated cisplatin-induced cytotoxicity in the patient-derived cells. Conclusions These results indicate BCAP31 dysfunction as a potential cause of transient ANSD, progressing to sensorineural hearing loss through mitochondrial impairment. Furthermore, they highlighted the therapeutic potential of allogenic mitochondrial transplantation as a novel strategy for treating hearing loss with an underlying component of mitochondrial dysfunction. This study contributes to the understanding of BCAP31’s role in auditory neuropathy and mitochondrial health. Graphical Abstracthttps://doi.org/10.1186/s12967-025-06610-3BAP31/BCAP31Hearing lossMitochondriaTransplantationApoptosis |
| spellingShingle | Yehree Kim Yujin Kim Bong Jik Kim Shin-Hye Yu Jin Hee Han Minyoung Kim Nayoung Yi Seo-Eun Lee Ju Ang Kim Kyuboem Han Chun-Hyung Kim Young Cheol Kang Byung Yoon Choi A novel BCAP31 variant associated with nonsyndromic auditory neuropathy spectrum disorder: mitochondrial dysfunction, cisplatin sensitivity, and amenability to mitochondrial transplantation Journal of Translational Medicine BAP31/BCAP31 Hearing loss Mitochondria Transplantation Apoptosis |
| title | A novel BCAP31 variant associated with nonsyndromic auditory neuropathy spectrum disorder: mitochondrial dysfunction, cisplatin sensitivity, and amenability to mitochondrial transplantation |
| title_full | A novel BCAP31 variant associated with nonsyndromic auditory neuropathy spectrum disorder: mitochondrial dysfunction, cisplatin sensitivity, and amenability to mitochondrial transplantation |
| title_fullStr | A novel BCAP31 variant associated with nonsyndromic auditory neuropathy spectrum disorder: mitochondrial dysfunction, cisplatin sensitivity, and amenability to mitochondrial transplantation |
| title_full_unstemmed | A novel BCAP31 variant associated with nonsyndromic auditory neuropathy spectrum disorder: mitochondrial dysfunction, cisplatin sensitivity, and amenability to mitochondrial transplantation |
| title_short | A novel BCAP31 variant associated with nonsyndromic auditory neuropathy spectrum disorder: mitochondrial dysfunction, cisplatin sensitivity, and amenability to mitochondrial transplantation |
| title_sort | novel bcap31 variant associated with nonsyndromic auditory neuropathy spectrum disorder mitochondrial dysfunction cisplatin sensitivity and amenability to mitochondrial transplantation |
| topic | BAP31/BCAP31 Hearing loss Mitochondria Transplantation Apoptosis |
| url | https://doi.org/10.1186/s12967-025-06610-3 |
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