Noise-induced hearing loss due to pejvakin defect: from pathogenesis to treatment

Mutations of PJVK, which encodes pejvakin, a protein of unknown function present only in vertebrates, cause the DFNB59 recessive form of sensorineural hearing impairment. In the first patients described, the impairment was restricted to neurons of the auditory pathway, as demonstrated by the combination of abnormal auditory brainstem responses (ABRs) with decreased wave amplitudes and increased inter- wave latencies. However, some DFNB59 patients were found to have a cochlear dysfunction, as shown by an absence of the otoacoustic emissions (OAEs). These patients had truncating mutations of PJVK, whereas the previously identified patients had missense mutations (p.T54I or p.R183W). However, the identification of patients also carrying the p.R183W missense mutation but lacking OAEs refuted any straightforward connection between the nature of the PJVK mutation and the hearing phenotype. The severity of deafness in DFNB59 patients varies from moderate to profound, and may even be progressive in some patients, suggesting that extrinsic factors may influence the hearing phenotype.
We investigated the role of pejvakin, with the aim of determining the origin of the phenotypic variability of the DFNB59 form of deafness. Our study of Pjvk knockout mouse models and of patients revealed an unprecedented hypervulnerability of auditory hair cells and neurons to sound- exposure, accounting for phenotypic variability. We found that pejvakin is a peroxisome-associated protein involved in the oxidative stress-induced proliferation of this organelle. Pejvakin-deficient mice revealed the key role of peroxisomes in the redox homeostasis of the auditory system and in the protection against noise-induced hearing loss.