Researchers cannot turn a deaf ear toward hearing loss, which is the most common sensory impairment in people. Previous studies identified dominant mutations that cause morphological defects in auditory development. However, many deaf people do not show gross morphological phenotypes. Now Schwander et al. report recessive mutations in cochlear hair cells that associate with deafness in a recent article in the Journal of Neuroscience.
Sound waves mechanically deflect stereocilia on hair cells in the cochlea, opening ion channels and translating sound into an electrical stimulus. Hair cells send electrical stimuli out of the cochlea, through the auditory nerve and into the brain. Defects in this circuit cause sensorineural deafness, the most common type of deafness in people.
To identify recessive genes associated with hereditary deafness, the authors used a forward genetic screen. They mutagenized male mice with N-ethyl-N-nitrosourea (ENU), which randomly produces point mutations, and crossed them with wild-type female mice. Researchers looking for dominant mutations test the resulting F1 founder generation. Because the authors were interested in recessive mutations, they mated F1 males to wild-type females and mated the resulting F2 females back to F1 founder males. They tested adult F3 offspring from 850 mouse lines. The authors stimulated auditory neurons with click sounds and recorded electrophysiological response in brainstem neurons. Sixteen mouse lines showed severe hearing impairment, and three mouse lines showed moderate impairment.
Several mouse lines had mutations that affected hair cell morphology and mapped to genes previously associated with hereditary deafness. The authors identified point mutations in Mass1, which is important in maintaining stereocilia, in Myo6, which is involved in intracellular transport, and in otoferlin, which encodes a calcium-binding protein.
Pejvakin mutation caused deafness without affecting auditory morphology. The authors identified an A-to-T substitution that introduced a stop codon in pejvakin, truncating its protein product before a zinc-finger domain. In situ hybridization localized pejvakin expression to hair cells. However, pejvakin mutant mice had normal auditory histology and hair cell morphology. Auditory brainstem response assays showed moderate hearing loss in three-week-old and severe hearing loss in eight-week-old pejvakin mutant mice, suggesting that the pejvakin mutation caused progressive hearing loss. Otoacoustic emissions are sounds made by the mechanical activity of hair cells. Wild-type but not pejvakin mutant mice showed distorted otoacoustic emissions when two tones played at once, suggesting that hair cell activity is impaired in pejvakin mutant mice.
Previous studies showed missense mutations in pejvakin associated with auditory neuropathy in people with normal cochlear function. However, the authors of the current study found hair cell and vestibular defects in mice with a point mutation in pejvakin. Do different mutations in pejvakin cause distinct types of deafness? The authors mapped progressive hearing impairment in an Iranian family to a pejvakin mutation that truncated pejvakin protein before its zinc-finger domain.
The authors identified a new genetic mutation associated with progressive deafness in people. Because pejvakin mutant mice had normal auditory morphology and therefore normal auditory development, these data suggest that gene therapy might be a workable strategy for treating certain types of deafness.