Hearing impairments are the most common symptom of congenital defects, and they generally remain intractable to treatment. Pendred syndrome, the most frequent syndromic form of hereditary hearing loss, is associated with mutations in the anion exchanger pendrin. Loss of pendrin function as an anion exchanger is thought to be causative, but rodent models do not exhibit progressive deafness. Here, we report a degenerative phenotype exhibiting mutant pendrin aggregates and increased susceptibility to cellular stresses in cochlear epithelial cells induced from patient-derived induced pluripotent stem cells (iPSCs). These degenerative phenotypes were rescued by site-specific gene corrections. Moreover, low-dose rapamycin and metformin reduced aggregation and cell death. Our results provide an unexpected, comprehensive understanding of deafness due to "degenerative cochlear disease" and may contribute to rational therapeutic development. This iPSC-based disease model provides an approach to the study of pathogenesis and therapeutic development for hereditary hearing loss.

Auditory neuropathy is a hearing disorder characterized by normal outer hair cell function and abnormal neural conduction of the auditory pathway. Aetiology and clinical presentation of congenital or early-onset auditory neuropathy are heterogeneous, and their correlations are not well understood. Genetic backgrounds and associated phenotypes of congenital or early-onset auditory neuropathy were investigated by systematically screening a cohort of 23 patients from unrelated Japanese families. Of the 23 patients, 13 (56.5%) had biallelic mutations in OTOF, whereas little or no association was detected with GJB2 or PJVK, respectively. Nine different mutations of OTOF were detected, and seven of them were novel. p.R1939Q, which was previously reported in one family in the United States, was found in 13 of the 23 patients (56.5%), and a founder effect was determined for this mutation. p.R1939Q homozygotes and compound heterozygotes of p.R1939Q and truncating mutations or a putative splice site mutation presented with stable, and severe-to-profound hearing loss with a flat or gently sloping audiogram, whereas patients who had non-truncating mutations except for p.R1939Q presented with moderate hearing loss with a steeply sloping, gently sloping or flat audiogram, or temperature-sensitive auditory neuropathy. These results support the clinical significance of comprehensive mutation screening for auditory neuropathy.

The present large-scale clinical survey revealed current epidemiological trends for idiopathic sudden sensorineural hearing loss (SSNHL) and various factors associated with the severity of hearing impairment and prognosis.

Cochlear fibrocytes play important roles in normal hearing as well as in several types of sensorineural hearing loss attributable to inner ear homeostasis disorders. Recently, we developed a novel rat model of acute sensorineural hearing loss attributable to fibrocyte dysfunction induced by a mitochondrial toxin. In this model, we demonstrate active regeneration of the cochlear fibrocytes after severe focal apoptosis without any changes in the organ of Corti. To rescue the residual hearing loss, we transplanted mesenchymal stem cells into the lateral semicircular canal; a number of these stem cells were then detected in the injured area in the lateral wall. Rats with transplanted mesenchymal stem cells in the lateral wall demonstrated a significantly higher hearing recovery ratio than controls. The mesenchymal stem cells in the lateral wall also showed connexin 26 and connexin 30 immunostaining reminiscent of gap junctions between neighboring cells. These results indicate that reorganization of the cochlear fibrocytes leads to hearing recovery after acute sensorineural hearing loss in this model and suggest that mesenchymal stem cell transplantation into the inner ear may be a promising therapy for patients with sensorineural hearing loss attributable to degeneration of cochlear fibrocytes. Mammalian cochlear fibrocytes of the mesenchymal nonsensory regions play important roles in the cochlear physiology of hearing, including the transport of potassium ions to generate an endocochlear potential in the endolymph that is essential for the transduction of sound by hair cells.1-3 It has been postulated that a potassium recycling pathway toward the stria vascularis via fibrocytes in the cochlear lateral wall is critical for proper hearing, although the exact mechanism has not been definitively determined.2 One candidate model for this ion transport system consists of an extracellular flow of potassium ions through the scala tympani and scala vestibuli and a transcellular flow through the organ of Corti, supporting cells, and cells of the lateral wall.4,5 The fibrocytes within the cochlear lateral wall are divided into type I to V based on their structural features, immunostaining patterns, and general location.5 Type II, type IV, and type V fibrocytes resorb potassium ions from the surrounding perilymph and from outer sulcus cells via the Na,KATPase. The potassium ions are then transported to type I fibrocytes, strial basal cells, and intermediate cells through gap junctions and are secreted into the intrastrial space through potassium channels. The secreted potassium ions are incorporated into marginal cells by the Na,K-ATPase and the Na-K-Cl co-transporter, and are finally secreted into the endolymph through potassium channels.Degeneration and alteration of the cochlear fibrocytes have been reported to cause hearing loss without any other changes in the cochlea in the Pit-Oct-Unc (POU)-domain transcription factor Brain-4 (Brn-4)-deficient mouse 6 and the otospiralin-deficient mouse.3 Brn-4 is the gene responsible f...