Journal Club: Prestin electromotility and phenotype in mouse model of human prestin variants

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Today's journal article

Takahashi S, Zhou Y, Dépreux F, Whitlon DS, Cheatham MA, Homma K. Hearing Loss and Audiogenic Seizures Induced by Hypofunctional Prestin Variants. 

Why I picked this article

Healthy hearing depends on tiny sensory cells in the inner ear called hair cells. There are two types of hair cells, outer and inner hair cells. Of those, outer hair cells act like microscopic motors: they change length in response to voltage. The end result of this is amplification of sound and sharpening frequency selectivity, so we can hear soft sounds and separate similar pitches. The protein called "prestin" sits in the outer hair cell membrane and powers this electromotility.

When prestin is completely absent, hearing sensitivity drops by about 50 dB across different frequencies, resulting in a severe hearing loss. Prestin is produced from the gene SLC26A5. Variants in SLC26A5 can cause a familial form of hearing loss, DFNB61. However, the exact relationship between dysfunction of prestin, reduced ability of outer hair cells' motor activity and hearing loss is not yet clear. If a partial function is enough, patients with certain genetic variants might benefit from modest boosts in prestin expression or trafficking rather than full replacement.

This research focused on two human deafness-associated prestin variants to estimate the minimal electromotility required for cochlear performance and explored downstream effects on hearing sensitivity.

Some of the research findings

Models
  • FVB/NJ mouse background 
  • Prestin variants p.A100T 
  • Prestin variant p.P119S 
  • homozygous - homozygous for one of the variant alleles
  • compound heterozygous; one copy each of p.A100T variant and p.P119S variant
Methods:
  • OHC electromotility: whole-cell recording on isolated outer hair cells.
  • Hearing metrics: auditory brainstem response across frequency; distortion product otoacoustic emission
  • Behavior/central readout: audiogenic seizure susceptibility.
Key results: 
  • Electromotility amplitude of outer hair cells: reduced by 70–80% with both variants; motor remains fast but less abundant in the membrane.
  • Hearing phenotype: mice homozygous for either p.A100T variant or p.P119S variants, or the compound heterozygous group, developed hearing loss by 20-day-old, and further progressed to be more severe by 36-40-day-old. 
  • Hearing loss was milder in the lower frequencies. 
  • Consistent with hearing loss, outer hair cell death was observed in the above mice. 
  • Outer hair cells isolated from mice homozygous for either p.A100T variant or p.P119S variants, or the compound heterozygous group showed less electromotility (hair cell length change). 
  • Characterisation and comparison of the membrane properties of outer hair cells suggest that prestins are very abundant at a young age, and prestin variants result in less and less prestin protein present in the membrane. 
A peculiar observation was that some mice suffered accidental death during the experiment. After further observation and investigations, researchers identified that mice with prestin variants likely suffered from sound-evoked seizures. They have investigated this further to conclude "By 1 month of age, most p.A100T homozygotes, compound heterozygotes, and all the p.P119S homozygotes underwent seizures, whereas none of the heterozygotes and WTmice did (Fig. 8, middle). By 2 months of age, fewer fractions of p.A100T and p.P119S homozygotes exhibited seizure phenotypes, and none of the compound heterozygotes responded (Fig. 8, right). This is likely due to the reduced input from the cochlea" 
Part of Figure 5A. Isolated outer hair cells from wild type (+/+) and prestin variant (A100T/A100T) mice. Takahashi et al. 2025

Haruna's takeaway

This is a very focused in vivo experimentation to study how prestin gene variants cause hearing loss. One key thing I thought was interesting is that the investigation of the observation of animals led to the discovery of seizures associated with these prestin variants. Researchers noted that acoustic seizures have been observed in other deafness mouse models and discussed this as potentially arising from altered neural processing in the central auditory system. It's great that researchers have paid attention to unexpected death, investigated further and clearly shared in the research manuscript - very much appreciated by the research community. 

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This is Haruna's 55/100 of the 100-day challenge to post a science blog article every day! I love inner ear biology & cochlear physiology.