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Genetic Contributions to Age-Related Hearing Loss

Steyger, Peter S., PhD; Garinis, Angela C., PhD

doi: 10.1097/01.HJ.0000559494.36685.b4
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Dr. Steyger, left, is a professor of otolaryngology–head and neck surgery at the Oregon Health & Science University. In June 2019, Dr. Steyger will become the director of the Translational Hearing Center in the department of biomedical sciences at Creighton University in Omaha, Nebraska. Dr. Garinis is an instructor in otolaryngology–head and neck surgery at the Oregon Health & Science University.

Age-related hearing loss (presbycusis) affects one in three adults between 64 and 75 years old and nearly half of adults over 75 years old in the United States.1 The consequences of hearing loss are typically detrimental, particularly in the elderly, reducing overall quality of life and accelerating the rate of cognitive decline. To date, scientists have not provided evidence of strategies to prevent presbycusis. However, emerging preclinical studies to reduce factors that contribute to the rate of hearing loss, such as reducing exposure to noise to preserve synaptic strength, are very encouraging.2

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The inner ear contains the cochlea and the vestibular system, which has sensory cells characterized by an apical hair (stereociliary) bundle and a cuticular plate. Traditionally, many scientists interested in hair cell physiology have focused their research efforts on the mechanotransducing properties of the hair cell bundle, and paid less attention to the cuticular plate anchoring the hair bundle. Du, et al., recently discovered that a sensory cell protein called LIM-only protein 7 (LMO7) plays a vital role in ensuring sensory cell resiliency and mechanotransduction over time.3

The authors have demonstrated that murine LMO7 first appears during the morphogenesis of the cuticular plate and the intercellular junctions of inner ear sensory cells at embryonic day 16 (of 20), and its expression increases over time, then plateaus after onset of hearing (∼post-natal day 16). Using green fluorescent protein (GFP) to tag endogenous LMO7, they confirmed the principal (immuno) localization of LMO7 to the cuticular plate. This was crucial to demonstrate that (at least) hair cell LMO7 did not have other functions such as nucleocytoplasmic shuttling to regulate transcription of selected proteins, as described in other cell types.

The authors used CRISPR/Cas9 gene editing tools to generate mice lacking exon 17 in LM07 (Lmo7 exon 17 KO) to eliminate multiple isoforms of LMO7. They observed a loss of immunoreactivity in cochlear and vestibular hair cells, and verified this using two independent antibodies to LMO7 via immunoblotting. Lmo7 exon 17 KO mice were viable and fertile, with no apparent gross morphological phenotypes. However, higher-resolution confocal microscopy revealed diminished deposition of filamentous actin crucial to the formation of the cuticular plate. The presence of actin filaments in the cuticular plate continued to diminish in the cochlear outer hair cells (OHCs), but not in the inner hair cells (IHCs), as the mice aged. The rootlets of stereocilia that emanate from the base and into the cuticular plate were also affected, showing greater variability in OHCs of Lmo7 exon 17 KO mice than in wildtype mice. In IHCs, rootlets were significantly shorter and thinner. Stereociliary rootlets are essential for optimal mechanotransduction and sensitive hearing in mice and humans.

Since LMO7 is important in the development of the cuticular plate and optimal hearing, the authors sought to find out if LMO7 interacted with other cuticular plate proteins. Using a co-immunoprecipitation strategy, they identified approximately 500 binding ligands, including LMO7 as it dimerizes. Other vital (actin-associated) proteins included several spectrins, non-muscle myosin II, and α-actinin. The authors also identified specific regions of LMO7 that interacted with actin filaments in cultured cell lines and, notably, organized and condensed actin filaments into dense networks that co-localized with the three aforementioned actin-associated proteins. These data imply that LMO7 cross-links actin filaments into a dense network and serves as a scaffold interacting with other actin-associated proteins.

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Disruption of this actiniferous network was hypothesized to interfere with sensitive hearing. To test this hypothesis, they obtained micromechanical measurements from within the cochlea, and these were found to be disrupted at the surface of sensory epithelium of Lmo7 exon 17 KO mice compared with wildtype mice at post-natal day 30. Nonetheless, Lmo7 exon 17 KO mice appear to have typical measures of murine auditory function until 11 weeks of age, before thresholds for both auditory brainstem responses and distortion product otoacoustic emissions were significantly elevated at 17 weeks of age and progressively worsened to near-profound hearing loss by 26 weeks of age. Intriguingly, the lower frequencies were more affected in Lmo7 exon 17 KO mice in contrast to many other murine models of hearing loss where the higher frequencies were progressively affected first.

Surprisingly, these functional phenotypic changes were not the result of sensory cell loss, and thus likely due to changes within the hair cells. To examine this more closely, the authors found that sensory cell uptake of gentamicin that preferentially permeates through the mechanoelectrical transduction channel was significantly reduced in older mice, implying the presence of a dysfunctional hair bundle and therefore mechanoelectrical transduction. High-resolution scanning electron microscopy revealed that, anatomically, Lmo7 exon 17 KO mice had apparently normal hair bundle morphology, but typical hair bundle morphology deteriorated by 26 weeks of age, with fused stereocilia or loss of “tenting” ascribed to the presence of tip-links crucial for mechanoelectrical transduction. These changes were especially present in IHCs near the apex of the cochlea, but were also present to a lesser extent in other regions of the cochlea and in OHCs.

Thus, the Lmo7 exon 17 KO mouse model of hearing loss is representative of abnormalities in the cuticular plate (and less so in stereocilia) that can result in progressive hearing loss and reduced cochlear tuning. The authors demonstrated that LMO7 is required in sustaining the typical morphologies of the cuticular plate and hair bundle necessary for life-long hearing in the absence of other insults. It will be interesting to learn whether exposure to higher-level sound intensities or ototoxins accelerate the onset of hearing loss in this mouse model. Future studies can also examine how other genetic markers for healthy hearing or age-related hearing loss are modulated in this particular preclinical model. These data will provide better understanding of the critical factors that contribute to presbycusis.

Du, T.T., Dewey, J.B., Wagner, E.L., Cui, R., Heo, J., Park, J.J., Francis, S.P., Perez-Reyes, E., Guillot, S.J., Sherman, N.E., Xu, W., Oghalai, J.S., Kachar, B., and Shin, J.B. (2019). LMO7 deficiency reveals the significance of the cuticular plate for hearing function. Nat Commun 10, 1117.

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1. NIDCD 2018 Age-Related Hearing loss. Retrieved from:
2. Kujawa & Liberman (2019). Translating animal models to human therapeutics in noise-induced and age-related hearing loss. Hear Res, 15 377: 44-52.
3. Du, T.T., Dewey, J.B., Wagner, E.L., Cui, R., Heo, J., Park, J.J., Francis, S.P., Perez-Reyes, E., Guillot, S.J., Sherman, N.E., Xu, W., Oghalai, J.S., Kachar, B., and Shin, J.B. (2019). LMO7 deficiency reveals the significance of the cuticular plate for hearing function. Nat Commun 10, 1117.
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