DFNB9: The first deafness ever treated by gene therapy

These are headlines you have likely read last January. The technology making this achievement possible rightfully took the spotlight (even I chimed in!). But what is DFNB9 deafness in the first place? Why do DFNB9 patients lose their hearing?

In a nutshell, DFNB9 deafness is the failure of the ear to share what it has heard with the brain because of mutations in the OTOF gene. 

Do you want to learn more? Let me explain.

Medical and genetic definitions of DFNB9 deafness

DFNB9 is a type of genetic deafness. It affects 1 to 16 newborns every 50,000, and it accounts for 2 to 8% of all cases of genetic deafness.

DFNB9 is (take a deep breath!) an autosomal recessive prelingual severe-to-profound non-syndromic sensorineural hearing loss. That’s a mouthful of a definition, I agree. Let’s break it down.

In medical terms, DFNB9 deafness is:

• severe — sounds must be louder than 70 dB (think of a vacuum cleaner) to be heard — to profound — sounds must be even louder, over 90 dB (picture a lawn mower),

• prelingual, that is hearing is lost before developing language skills (2–3 years of age)

• not associated with other pathologies (non-syndromic).

  
  

Geneticists describe DFNB9 as an autosomal recessive disease: the gene mutated is not on the sex chromosomes (but on the autosomes) and both alleles must be mutated for the disease to appear (recessive). This gene is OTOF. OTOF encodes otoferlin, a protein that enables the cells detecting sounds to communicate with neurons. As mutations in OTOF disrupt this dialogue, DFNB9 is classified as a sensorineural type of deafness.

Otoferlin enables inner hair cells to speak to neurons

How does otoferlin enable us to hear? This question needs a few notions on the two main cell types involved in hearing: auditory hair cells and primary auditory neurons.

• Auditory hair cells are the sound detector. These cells are surmounted by a structure resembling a tuft of hair, the hair bundle. Sounds bend the hair bundle, opening its ion channels; positive ions rush into the cells generating electrical signals that travel across the cell. Inner hair cells — one of the two types of auditory cells — transmit these signals to the primary auditory neurons (Figure 1)

  
  

• The primary auditory neurons are the first station of the nervous pathway between the ear and the brain. Some primary auditory neurons (type I) extend their dendrites to the inner hair cells and listen. The information received is analysed and sent to the brain along the auditory nerve (Figure 2).

The synapse is where inner hair cells speak to primary auditory neurons. Otoferlin is essential for this dialogue: without it, inner hair cells cannot share what they have heard.

Otoferlin, the calcium sensor

At the synapse, synaptic vesicles are placed just beneath the membrane, like Formula 1 cars lined up the grid waiting for the race to start. In response to a sound, electrical signals trigger the opening of calcium channels and calcium ions (Ca2+) rush in. The sudden increase in Ca2+ is the biological equivalent of the “lights out” signal in Formula 1: as soon as Ca2+ enters, the synaptic vesicles rapidly fuse with the membrane. This event releases glutamate onto the primary auditory neurons (Figure 3). The information in the sound is on its way to the brain.

In the inner hair cells, otoferlin enables synaptic vesicles to sense changes in Ca2+. Anchored to the vesicles by its tail, otoferlin extends into the cell multiple regions with high affinity to Ca2+ (C2 domains) (Figure 4).

The many roles of otoferlin at the synapse

Otoferlin is essential throughout the lifecycle of synaptic vesicles (Figure 5). This is a brief overview of its main roles at the synapse:

1 — Docking: Otoferlin helps position vesicles filled with glutamate at the synapse 

2 — Priming: Otoferlin interacts with SNARE proteins, which are essential for the fusion with the membrane, and the vesicles become ready to rapidly fuse

3 — Fusion: electrical signals, triggered by sounds, open Ca2+ channels; Otoferlin senses the increase in Ca2+ and prompts the vesicles to fuse with the cell membrane, releasing glutamate

4 — Recycling: Otoferlin helps clear fused vesicles and recycle their components 

Imperfect knowledge can be enough knowlege (sometimes)

Despite years of studies, the functions of otoferlin at the inner hair cell synapse are still elusive. Even more puzzling is the synapse of inner hair cells as a whole. Researchers are captivated and baffled by its mysterious architecture and properties (we would need a new article just to scratch the surface of this topic!).

But let’s not forget that we now have two gene therapies to improve the deafness caused by mutations in the OTOF gene. These breakthroughs should encourage us: even with imperfect knowledge, we can (at least in some cases) still develop impactful treatments for diseases.

Written by Matteo Cortese, PhD

REFERENCES

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