A novel BCAP31 variant associated with nonsyndromic auditory neuropathy spectrum disorder: mitochondrial dysfunction, cisplatin sensitivity, and amenability to mitochondrial transplantation.

backgroundA 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).

methodsExome 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).

resultsANSD 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.

conclusionsThese 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.