Otoferlin

Otoferlin is a protein that in humans is encoded by the OTOF gene. It plays a critical role in the inner ear for synaptic transmission of sound information from hair cells to auditory nerve fibers. Otoferlin is essential for the efficient release of neurotransmitters at ribbon synapses in cochlear hair cells, facilitating the encoding of sound signals into nerve impulses. Mutations in the OTOF gene are associated with a form of sensorineural hearing loss, specifically non-syndromic recessive deafness known as DFNB9.

Function

Otoferlin functions as a calcium sensor and is involved in the exocytosis of synaptic vesicles in auditory hair cells. It is crucial for the synaptic vesicle replenishment and the release process, enabling hair cells to convert mechanical sound vibrations into electrical signals. This process is vital for hearing, as it allows the transmission of sound information from the cochlea to the brain.

Genetics

The OTOF gene is located on the long (q) arm of chromosome 2 at position 2p23.3. Mutations in this gene can lead to impaired synaptic function in the cochlea, resulting in hearing loss. Over 100 mutations in the OTOF gene have been identified, which can cause non-syndromic hearing loss DFNB9. These mutations can lead to the production of an abnormal otoferlin protein that cannot perform its role in neurotransmitter release, disrupting auditory signal transmission.

Clinical Significance

Hearing loss associated with OTOF gene mutations is typically congenital, bilateral, and ranges from moderate to profound. The hearing impairment is due to a defect in the sound-evoked neurotransmitter release at the ribbon synapses of cochlear inner hair cells. Diagnosis of otoferlin-related hearing loss can be confirmed through genetic testing, identifying mutations in the OTOF gene.

Treatment and Management

Currently, there is no cure for hearing loss caused by mutations in the OTOF gene. Management strategies focus on mitigating the impact of hearing loss on communication and quality of life. These may include the use of hearing aids, cochlear implants, and other assistive listening devices, along with speech therapy and other educational interventions.

Research Directions

Research on otoferlin is ongoing, with studies aimed at understanding its precise role in auditory processing and exploring potential therapeutic targets. Gene therapy is one promising area of research, where correcting the defective OTOF gene or introducing a functional copy of the gene into the inner ear could potentially restore normal hearing.