Genetics of Age-Related Hearing Loss

Aguilar Hernández, Carlos Francisco (2022). Genetics of Age-Related Hearing Loss. PhD thesis The Open University.



Age-Related Hearing Loss (ARHL) is a prevalent condition (>25% of those aged ≥70-years) associated with depression and cognitive decline. Our ignorance of the genetics of ARHL is an impediment to the development of therapies to ameliorate this aliment. To advance the genetic dissection of ARHL, I have employed a reverse genetics approach characterising mouse mutants for candidate genes arising from human Genome-Wide Association Studies (GWAS) and Exome Sequencing of affected families. Additionally, I have employed a forward genetics approach utilising the Harwell Ageing Screen to identify mouse mutants exhibiting progressive and late-onset deafness.

Firstly, utilising human GWAS data, knockout mutants were generated and characterised for genes showing association with hearing difficulty. This identified Klhdc7b as a novel deafness gene, with mice exhibiting an early, progressive hearing loss with hair bundle abnormalities. In addition, possible sound-transmission issues were identified in two knockout models (Grm7 and Arhgef28).

Secondly, in order to validate mutations identified in ARHL families, bespoke knock-in mouse mutants were generated and characterised. Using this approach, an Ap3m2-L157P mutant was generated along with a frame-shifting ‘null’ mutant (Ap3m2-Ins1). While the Ap3m2-L157P mutant does not have an overt hearing phenotype, the null mice have a moderate stable deafness that could be due to issues with the synaptic vesicles in Inner hair cells.

Thirdly, from the Harwell Ageing Screen, I have identified a pedigree with a mutation in Rbbp5, a core component of the histone-methyltransferase-complex. This is the first report of deafness due to a mutation in an epigenetic effector. These mice show signs of hair cell loss/dysfunction prior to an overt deafness phenotype.

In summary, I have successfully utilised a three-pronged approach to elaborate upon the genetics of ARHL, demonstrating the utility of the mouse for studying this condition. This knowledge will lay the foundations for developing therapeutic strategies to ameliorate progressive hearing loss and its comorbidities.

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