The cells of the sensory epithelium, and not the stria vascularis, are the main cochlear cells related to the genetic pathogenesis of age-related hearing loss

Eshel, Mai; Milon, Beatrice; Hertzano, Ronna; Elkon, Ran

doi:10.1016/j.ajhg.2024.01.008

Cited by 3 publications

(1 citation statement)

References 21 publications

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“…We conclude from this high expression across many cell types in the inner ear that the MD network + recurrent prioritized genes may play key roles across the ear in Ménière's Disease, and that the disorder may be both polygenic and poly-cellular. However, we acknowledge that this dataset lacks broad representation of all cell types in the human cochlea [ 38 ] and further study of a representative single cell atlas is warranted.…”

Section: Resultsmentioning

confidence: 99%

The genomic landscape of Ménière's disease: a path to endolymphatic hydrops

Fisch,

Rosenthal,

Mark

et al. 2024

BMC Genomics

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Background Ménière's disease (MD) is a disorder of the inner ear that causes episodic bouts of severe dizziness, roaring tinnitus, and fluctuating hearing loss. To date, no targeted therapy exists. As such, we have undertaken a large whole genome sequencing study on carefully phenotyped unilateral MD patients with the goal of gene/pathway discovery and a move towards targeted intervention. This study was a retrospective review of patients with a history of Ménière's disease. Genomic DNA, acquired from saliva samples, was purified and subjected to whole genome sequencing. Results Stringent variant calling, performed on 511 samples passing quality checks, followed by gene-based filtering by recurrence and proximity in molecular interaction networks, led to 481 high priority MD genes. These high priority genes, including MPHOSPH8, MYO18A, TRIOBP, OTOGL, TNC, and MYO6, were previously implicated in hearing loss, balance, and cochlear function, and were significantly enriched in common variant studies of hearing loss. Validation in an independent MD cohort confirmed 82 recurrent genes. Pathway analysis pointed to cell–cell adhesion, extracellular matrix, and cellular energy maintenance as key mediators of MD. Furthermore, the MD-prioritized genes were highly expressed in human inner ear hair cells and dark/vestibular cells, and were differentially expressed in a mouse model of hearing loss. Conclusion By enabling the development of model systems that may lead to targeted therapies and MD screening panels, the genes and variants identified in this study will inform diagnosis and treatment of MD.

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Section: Resultsmentioning

confidence: 99%

The genomic landscape of Ménière's disease: a path to endolymphatic hydrops

Fisch,

Rosenthal,

Mark

et al. 2024

BMC Genomics

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Pharmacological Approaches to Hearing Loss

Cederroth,

Dyhrfjeld-Johnsen,

Canlon

2024

Pharmacol Rev

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Hearing disorders pose significant challenges to individuals experiencing them and their overall quality of life, emphasizing the critical need for advanced pharmacological approaches to address these conditions. Current treatment options often focus on amplification devices, cochlear implants, or other rehabilitative therapies, leaving a substantial gap regarding effective pharmacological interventions. Advancements in our understanding of the molecular and cellular mechanisms involved in hearing disorders induced by noise, aging, and ototoxicity have opened new avenues for drug development, some of which have led to numerous clinical trials, with promising results. The development of optimal drug delivery solutions in animals and humans can also enhance the targeted delivery of medications to the ear. Moreover, large genome studies contributing to a genetic understanding of hearing loss in humans combined with advanced molecular technologies in animal studies have shown a great potential to increase our understanding of the etiologies of hearing loss. The auditory system exhibits circadian rhythms and temporal variations in its physiology, its vulnerability to auditory insults, and its responsiveness to drug treatments. The cochlear clock rhythms are under the control of the glucocorticoid system, and preclinical evidence suggests that the risk/benefit profile of hearing disorder treatments using chronopharmacological approaches would be beneficial. If translatable to the bedside, such approaches may improve the outcome of clinical trials. Ongoing research into the molecular and genetic basis of auditory disorders, coupled with advancements in drug formulation and delivery as well as optimized timing of drug administration, holds great promise of more effective treatments. Significance Statement Hearing disorders pose significant challenges to individuals and their overall quality of life, emphasizing the critical need for advanced pharmacological approaches to address these conditions. Ongoing research into the molecular and genetic basis of auditory disorders, coupled with advancements in drug delivery procedures and optimized timing of drug administration, holds the promise of more effective treatments.

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Common genetic etiologies of sensorineural hearing loss in Koreans

Jang,

Yoon,

Gee

2024

Genom. Inform.

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Hearing loss is the most common sensory disorder. Genetic factors contribute substantially to this condition, although allelic heterogeneity and variable expressivity make a definite molecular diagnosis challenging. To provide a brief overview of the genomic landscape of sensorineural hearing loss in Koreans, this article reviews the genetic etiologies of nonsyndromic hearing loss in Koreans as well as the clinical characteristics, genotype–phenotype correlations, and pathogenesis of hearing loss arising from common variants observed in this population. Furthermore, potential genetic factors associated with age-related hearing loss, identified through genome-wide association studies, are briefly discussed. Understanding these genetic etiologies is crucial for advancing precise molecular diagnoses and developing targeted therapeutic interventions for hearing loss.

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The cells of the sensory epithelium, and not the stria vascularis, are the main cochlear cells related to the genetic pathogenesis of age-related hearing loss

Cited by 3 publications

References 21 publications

The genomic landscape of Ménière's disease: a path to endolymphatic hydrops

The genomic landscape of Ménière's disease: a path to endolymphatic hydrops

Pharmacological Approaches to Hearing Loss

Common genetic etiologies of sensorineural hearing loss in Koreans

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