Background: Hereditary hearing loss is one of the most common heterogeneous disorders, and genetic variants that can cause hearing loss have been identified in over sixty genes. Most of these hearing loss genes have been detected using classical genetic methods, typically starting with linkage analysis in large families with hereditary hearing loss. However, these classical strategies are not well suited for mutation analysis in smaller families who have insufficient genetic information. Methods: Eighty known hearing loss genes were selected and simultaneously sequenced by targeted next-generation sequencing (NGS) in 8 Korean families with autosomal dominant non-syndromic sensorineural hearing loss. Results: Five mutations in known hearing loss genes, including 1 nonsense and 4 missense mutations, were identified in 5 different genes (ACTG1, MYO1F, DIAPH1, POU4F3 and EYA4), and the genotypes for these mutations were consistent with the autosomal dominant inheritance pattern of hearing loss in each family. No mutational hot-spots were revealed in these Korean families. Conclusion: Targeted NGS allowed for the detection of pathogenic mutations in affected individuals who were not candidates for classical genetic studies. This report is the first documenting the effective use of an NGS technique to detect pathogenic mutations that underlie hearing loss in an East Asian population. Using this NGS technique to establish a database of common mutations in Korean patients with hearing loss and further data accumulation will contribute to the early diagnosis and fundamental therapies for hereditary hearing loss.

Aims: Methionine sulfoxide reductase B3 (MsrB3), which stereospecifically repairs methionine- R -sulfoxide, is an important Msr protein that is associated with auditory function in mammals. MsrB3 deficiency leads to profound congenital hearing loss due to the degeneration of stereociliary bundles and the apoptotic death of cochlear hair cells. In this study, we investigated a fundamental treatment strategy in an MsrB3 deficiency mouse model and confirmed the biological significance of MsrB3 in the inner ear using MsrB3 knockout ( MsrB3 ^−/− ) mice. Results: We delivered a recombinant adeno-associated virus encoding the MsrB3 gene directly into the otocyst at embryonic day 12.5 using a transuterine approach. We observed hearing recovery in the treated ears of MsrB3 ^−/− mice at postnatal day 28, and we confirmed MsrB3 mRNA and protein expression in cochlear extracts. Additionally, we demonstrated that the morphology of the stereociliary bundles in the rescued ears of MsrB3 ^−/− mice was similar to those in MsrB3 ^+/+ mice. Innovation: To our knowledge, this is the first study to demonstrate functional and morphological rescue of the hair cells of the inner ear in the MsrB3 deficiency mouse model of congenital genetic sensorineural hearing loss using an in utero , virus-mediated gene therapy approach. Conclusion: Our results provide insight into the role of MsrB3 in hearing function and bring us one step closer to hearing restoration as a fundamental therapy. Antioxid. Redox Signal. 24, 590–602.

Cisplatin, a small platinum-containing molecule, is a widely used, highly effective anticancer drug. However, severe side effects have been found in cancer patients treated with cisplatin, including nephrotoxicity, neurotoxicity, and ototoxicity. These cisplatin-induced side effects can have a major impact on patient quality of life, including social development problems in pediatric patients that develop hearing loss. Previous studies have suggested that the major cause of cisplatin-induced ototoxicity is abnormal accumulation of reactive oxygen species (ROS) and oxidative stress. Alpha-lipoic acid (ALA), one of the most effective antioxidants, is known to be involved in the cellular antioxidant system and may have a protective effect on cisplatin-induced ototoxicity. However, the therapeutic effect of ALA on damaged hearing function and its detailed mechanism of action are not fully understood. This study focused on determining whether ALA has a potential as a protective and/or therapeutic agent for cisplatin-induced ototoxicity. Histological and physiological analyses were performed using cisplatin-treated mouse cochlea and HEI-OC1 culture cells in pre- and post-treatment with ALA in vitro and in vivo. We found that ALA contributes to protecting mitochondrial function by preventing ROS accumulation and inhibiting apoptotic cell death. Importantly, post-treatment with ALA consistently showed an almost equal restorative effect to pretreatment, in vitro and in vivo, supporting the possible use of ALA as a therapeutic agent for cisplatin-induced ototoxicity. This study is the first report on a strong therapeutic potential of ALA to rescue ototoxic hearing loss caused by cisplatin, and our data provide key evidence that ALA may act as a reducing agent for glutathione disulfide to increase glutathione levels on behalf of glutathione reductase. This result was consistent in both cultured cells and the mouse model, which improves the clinical value of ALA for therapy of cisplatin-induced ototoxicity.

We have developed a method to monitor the activities of human taste receptor protein in lipid membrane using carbon nanotube transistors, enabling a “bioelectronic super-taster (BST)”, a taste sensor with human-tongue-like selectivity. In this work, human bitter taste receptor protein expressed in E. coli was immobilized on a single-walled carbon nanotube field effect transistor (swCNT-FET) with the lipid membrane. Then, the protein binding activity was monitored using the underlying swCNT-FET, leading to the operation as a BST device. The fabricated BST device could detect bitter tastants at 100 fM concentrations and distinguish between bitter and non-bitter tastants with similar chemical structures just like a human tongue. Furthermore, this strategy was utilized to differentiate the responses of taster or non-taster types of the bitter taste receptor proteins.