Silver, Benjamin Harry;
(2024)
Evaluation and characterisation of KLHDC7B in hearing loss.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Wells et al. (2019) conducted a genome-wide association study (GWAS) using the UK Biobank Cohort (UKBB) and identified 44 genes associated with self-reported hearing loss between ages 40 and 69 years. Amongst these, 34 genes were newly linked to auditory function, creating a candidate gene list for age-related hearing loss (ARHL). This represented a significant advancement compared to any previous GWAS investigations into ARHL. A post-GWAS pipeline was devised to explore these novel candidates, incorporating in-silico, in-vitro, and in-vivo methods. Kelch domain containing 7B (KLHDC7B) emerged as a particularly interesting, as it is an uncharacterised gene that harbours the lead SNP rs36062310. Additionally, various independent cochlea gene expression data confirmed it localised within the inner ear. KLHCD7B was prioritised as a candidate for knockout mouse model creation. Subsequently, the Klhdc7bdel1258/del1258 mouse model was identified to exhibit an early-onset progressive hearing loss. Klhdc7bdel1258/del1258 inner ear anatomy was analysed through wholemounts, vibratome sections, and immunostaining for specific markers. Cellular localisation was investigated using a plasmid vector containing a cloned KLHDC7B-eGFP-tagged protein of the minor and major alleles at SNP rs36062310. The missense mutation was analysed using 3D protein structure modelling. Taken together, these data confirm the role of KLHDC7B as a novel hearing loss gene suggesting its role in auditory protection. This work enhances our understanding of ARHL genetics and paves the way for potential therapeutic avenues. These findings will provide the basis of future work to identify the role of KLHDC7B within the cochlea.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Evaluation and characterisation of KLHDC7B in hearing loss |
| Language: | English |
| Additional information: | Copyright © The Author 2024. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > The Ear Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > UCL Medical School UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > UCL Medical School > Clinical and Professional Practice Unit UCL |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10198884 |
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