Abstract
The underlying causes of age-related hearing loss (ARHL) are not well understood, but it is clear from heritability estimates that genetics plays a role in addition to environmental factors. Genome-wide association studies (GWAS) in human populations can point to candidate genes that may be involved in ARHL, but follow-up analysis is needed to assess the role of these genes in the disease process. Some genetic variants may contribute a small amount to a disease, while other variants may have a large effect size, but the genetic architecture of ARHL is not yet well-defined. In this study, we asked if a set of 17 candidate genes highlighted by early GWAS reports of ARHL have detectable effects on hearing by knocking down expression levels of each gene in the mouse and analysing auditory function. We found two of the genes have an impact on hearing. Mutation of Dclk1 led to late-onset progressive increase in ABR thresholds and the A430005L14Rik (C1orf174) mutants showed worse recovery from noise-induced damage than controls. We did not detect any abnormal responses in the remaining 15 mutant lines either in thresholds or from our battery of suprathreshold ABR tests, and we discuss the possible reasons for this.
Highlights
Age-related progressive hearing loss (ARHL) is very common in the population and can begin at any age
doublecortin-like 1 (Dclk1) is involved in age-related progressive hearing loss
The mouse Dclk1 mutation knocked down mRNA expression of the gene (Fig. 1) which was associated with a progressive increase in Auditory brainstem response (ABR) thresholds from 14 weeks to 12 months old (Fig. 13), with heterozygotes showing an intermediate phenotype
Summary
Age-related progressive hearing loss (ARHL) is very common in the population and can begin at any age. Hearing impairment is profoundly isolating, both socially and economically, and has a major impact on the quality of life of those affected, often associated with depression or cognitive decline, and is a predictor of dementia Thresholds for detecting sound do not always reflect the degree of dysfunction experienced by people in the early stages of progressive hearing loss. Developing treatments will require knowledge of the molecular and cellular basis of ARHL, and genetics is a useful tool to give us insight into the molecular networks and pathways involved
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