Inner hair cell dysfunction in Klhl18 mutant mice leads to low frequency progressive hearing loss

Age-related hearing loss in humans (presbycusis) typically involves
impairment of high frequency sensitivity before becoming progressively
more severe at lower frequencies. Pathologies initially affecting lower
frequency regions of hearing are less common. Here we describe a
progressive, predominantly low-frequency recessive hearing impairment in
two mutant mouse lines carrying different mutant alleles of the Klhl18
gene: a spontaneous missense mutation (Klhl18lowf) and a targeted mutation
(Klhl18tm1a(KOMP)Wtsi). Both males and females were studied, and the two
mutant lines showed similar phenotypes. Threshold for auditory brainstem
responses (ABR; a measure of auditory nerve and brainstem neural activity)
were normal at 3 weeks old but showed progressive increases from 4 weeks
onwards. In contrast, distortion product otoacoustic emission (DPOAE)
sensitivity and amplitudes (a reflection of cochlear outer hair cell
function) remained normal in mutants. Electrophysiological recordings from
the round window of Klhl18lowf mutants at 6 weeks old revealed 1) raised
compound action potential thresholds that were similar to ABR thresholds,
2) cochlear microphonic potentials that were normal compared with wildtype
and heterozygous control mice and 3) summating potentials that were
reduced in amplitude compared to control mice. Scanning electron
microscopy showed that Klhl18lowf mutant mice had abnormally tapering of
the tips of inner hair cell stereocilia in the apical half of the cochlea
while their synapses appeared normal. These results suggest that Klhl18 is
necessary to maintain inner hair cell stereocilia and normal inner hair
cell function at low frequencies.