Abstract
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.
Highlights
Progressive hearing loss with age is the most common sensory deficit in the human population and it can begin at any age
The auditory brainstem response (ABR) is a convenient electrophysiological approach that can be recorded non-invasively, allowing us to track any changes in auditory responses in the same mouse as it ages
The presence of abnormal ABRs and Compound Action Potential (CAP) together with normal distortion product otoacoustic emissions (DPOAEs) and Cochlear Microphonic (CM) responses and normal Endocochlear Potential (EP) suggests that Klhl18 mutant mice exhibit an inner hair cells (IHCs) defect or neural hearing loss, so we looked in more detail at the neural elements of the organ of Corti
Summary
Progressive hearing loss with age is the most common sensory deficit in the human population and it can begin at any age. Genes found to be involved in hearing loss can give valuable insights into the molecular pathways and pathological processes leading to progressive deafness. Mouse mutants can provide valuable candidate genes for human deafness and reveal novel pathological mechanisms underlying hearing loss.
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