Ziff, JL; (2014) A molecular and genetic analysis of otosclerosis. Doctoral thesis , UCL (University College London).

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Abstract

Otosclerosis is a common form of conductive hearing loss. It is characterised by abnormal bone remodelling within the otic capsule, leading to formation of sclerotic lesions of the temporal bone. Encroachment of these lesions on to the footplate of the stapes in the middle ear leads to stapes fixation and subsequent conductive hearing loss. The hereditary nature of otosclerosis has long been recognised due to its recurrence within families, but its genetic aetiology is yet to be characterised. Although many familial linkage studies and candidate gene association studies to investigate the genetic nature of otosclerosis have been performed in recent years, progress in identifying disease causing genes has been slow. This is largely due to the highly heterogeneous nature of this condition. The research presented in this thesis examines the molecular and genetic basis of otosclerosis using two next generation sequencing technologies; RNA-sequencing and Whole Exome Sequencing. RNA–sequencing has provided human stapes transcriptomes for healthy and diseased stapes, and in combination with pathway analysis has helped identify genes and molecular processes dysregulated in otosclerotic tissue. Whole Exome Sequencing has been employed to investigate rare variants that segregate with otosclerosis in affected families, and has been followed by a variant filtering strategy, which has prioritised genes found to be dysregulated during RNA-sequencing. This has identified multiple variants predicted to be involved in splicing within genes involved in the bone disorder Osteogenesis Imperfecta, indicating a shared genetic aetiology for this condition and otosclerosis and a possible disease mechanism involving alternative splicing in the stapes. Whilst the hereditability of otosclerosis remains elusive, the identification of new candidate genes will make a significant contribution to the current literature. It is hoped that long term, this research will help reveal disease mechanisms and thereby improve treatment options for otosclerosis patients.

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