Reply: Both mitochondrial DNA and mitonuclear gene mutations cause hearing loss through cochlear dysfunction

Recently, we investigated the site of the lesion and the pathophysiological mechanisms behind the hearing impairment in patients carrying different mutations in the OPA1 gene (Santarelli et al., 2015). We found that subjects harboring missense mutations show the profile of auditory neuropathy, and that underlying the hearing impairment is a disordered synchrony in auditory fiber activity resulting from neural degeneration involving the terminal dendrites. One subject harboring the missense mutation c.869G>A, however, had cochlear hearing impairment resulting from hair cell loss and disruption of the cochlear amplifier. Interestingly, this mutation was associated with cochlear hearing dysfunction also in the patient described by Kullar et al. (2016). This may indicate that both the site and mechanism of the lesion behind hearing impairment might be related, to some extent, to specific OPA1 mutations. Moreover, in agreement with the findings reported by Kullar et al. (2016), our study showed that the OPA1 mutations inducing haploinsufficiency are associated with normal hearing or mild cochlear hearing loss.