LOXHD1, encoding lipoxygenase homology domain 1, is crucial for the mechanotransduction process in cochlear hair cells [2]. It consists of 15 polycystin lipoxygenase α -toxin (PLAT) repeats, which can bind lipids and proteins in other proteins. LOXHD1 is distributed along the length of stereocilia, and is essential for sound detection in the inner ear, as it helps transfer sound-induced forces to gate the mechanotransduction channels [2].

Two LOXHD1 mouse models with mutations in the 10th PLAT repeat exhibited mechanotransduction defects. In these mutants, while mechanotransduction currents in inner hair cells (IHCs) were similar to wild-type levels in the first postnatal week, they were severely affected by postnatal day 11. The onset of the mechanotransduction phenotype was consistent with the temporal progression of postnatal LOXHD1 expression/localization in the hair bundle. Also, LOXHD1 is indispensable for maintaining TMC1-pore forming subunits at the tip link, but is dispensable for TMC2. In LOXHD1's absence, TMC1 is mislocalized away from the force transmission site [2,3,4].

In conclusion, LOXHD1 plays a vital role in hair-cell mechanotransduction and normal hearing function. Mouse models with LOXHD1 mutations have revealed its essential function in keeping the auditory mechanosensitive channels at the site of force transmission. Mutations in LOXHD1 are associated with autosomal recessive nonsyndromic sensorineural hearing loss (NSHL), such as DFNB77, and can also cause auditory neuropathy spectrum disorder (ANSD), highlighting its significance in understanding genetic hearing loss [1,2,3,4,5].