What's hot about otoferlin

Abstract

Mutations in the otoferlin (OTOF) gene lead to profound hearing loss in humans. Interestingly, a number of missense otoferlin mutations cause hearing defects but only at higher body temperature, and the reasons for this have been elusive until now. A study published in this issue of The EMBO Journal (Strenzke et al, 2016) adds insight into the underlying mechanisms for this heat‐dependent hearing loss.

Figure 1. The link between otoferlin, heat and hearing loss

Auditory neuropathy (AN) is a relatively common form of hearing loss, accounting for approximately 10% of childhood deafness. Sensory hair cell activity, as measured by otoacoustic emissions representing mechanical amplification of outer hair cells, and cochlear microphonics, which examines electrical potentials of both inner and outer hair cells, is normal in AN patients. However, auditory nerve activity is compromised, as measured by auditory brainstem response (ABR). The speech discrimination score, which evaluates understanding of speech, is often low. Some patients with OTOF mutations suffer from an exacerbated hearing impairment when they have a fever. Surprisingly, mice with the same mutation retain the same level of hearing upon exposure to heat. Strenzke et al (2016) determined that the culprit of this difference lies in a 20‐amino acid RXR motif. Transfection of otoferlin cDNA with an OTOF mutation and RXR motif in cochlear cultures, introduced by a gene gun, demonstrated that otoferlin disappeared from the inner hair cell plasma membrane. The levels of plasma membrane‐bound otoferlin correlate with functional synaptic function and sound encoding. Note that the mutations c.1544T>C (p.Ile515Thr) and c.3346C>T (p.Arg1116*) are present in the long isoform of otoferlin (NP_001274418).