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Title: Genetic investigation of keratoconus
Author: Lechner , Judith
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2013
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Keratoconus is a bilateral, progressive corneal thinning disorder that is the leading indication for corneal transplantation in the developed world. Keratoconus usually arises in the teenage years and presents a significant health burden in work-age adults. The minimum incidence is 1 in 2000 but it is much more common in some ethnic groups. There is strong evidence for a heritable component in the development of keratoconus. Most studies describe autosomal dominant inheritance, with incomplete penetrance or variable expressivity. The genetic basis of KC provides an opportunity to apply molecular genetic and mapping approaches to elucidate the mechanisms responsible for the pathogenesis of keratoconus. Two main approaches have been applied in this project to investigate the genetic determinants of keratoconus: candidate gene sequencing and genome wide association study using single nucleotide polymorphisms (SNPs) followed by amplicon next generation sequencing of identified candidate genes. As a result of this project mutations in four genes CBS, ZNF469, ZES1 and MIR184 have been implicated in the development of keratoconus. In this study, mutations in ZNF469 have been identified in 11 .8% of keratoconus patients making ZNF469 the most significant genetic factor responsible for keratoconus to date. The identified genes provide further insight into the underlying biochemical processes and signalling pathways involved in keratoconus disease pathogenesis and highlight three main biological processes involved in disease development corneal wound healing (MIR184 and HGF), collagen regulation (ZNF469 and ZEB1) and oxidative stress defence (CBS). No specific treatment exists for keratoconus except to replace the corneal tissue by corneal transplantation when the visual acuity can no longer be corrected by contact lenses. Although photochemical treatments such as collagen cross-linking may prevent progression in selected individuals, they are unlikely to reverse the effects of established disease. Functional studies are required to establish how the identified genes and mutations contribute to the disease development in order to implement diagnostic tests, offer more accurate prognosis and develop novel therapies.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available