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Title: Molecular basis of inherited retinal degenerations
Author: Tulloch, Merrin E.
ISNI:       0000 0001 3537 6719
Awarding Body: Imperial College London (University of London)
Current Institution: Imperial College London
Date of Award: 2007
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Mutations of the REP-l gene are responsible for the X-linked retinal degeneration choroideremia (CHM). Rab Escort Protein-I (REP-I) mediates the post-translational prenyl modification of Rab GTPases. In CHM patients, the related REP-2 partly compensates for the loss-offunction of REP-I, but a subset of Rabs remain und~renylated and thus inactive. A zebrafish model of CHM exhibiting a truncating mutation in the orthologous gene has been recently isolated and reported to lead to early lethality. This thesis characterises the development of the retinal phenotype observed in homozygous chm zebrafish. The retina develops normally for the first 4dpf followed by a catastrophic multi-layer degeneration in the ensuing hours. The chm zebrafish also exhibit severe multi-systemic disease and die usually on the fifth day post fertilitsation. Bioinformatic analysis ofthe REP family of proteins revealed a single REP isofonn in fish, other non-mammalian vertebrates and invertebrates, suggesting that the intronless REP-2 resulted from gene duplication events within the mammalian lineage. Therefore REP may be considered to be an essential gene in zebrafish. In the chm zebrafish, maternally-derived functional REP allows initial successful development of the embryo, but by 5pdf only 40% of normal REP activity remains and unprenylated Rabs accumulate in the cytosol. This suggests the gradual loss of maternally-derived REP activity leads to the catastrophic phenotype and lethality observed. In its current form, the chm zebrafish has limited utility as a model for human disease. Introduction of REP-2 would yield a powerful model for CHM research. Alternatively, the chm zebrafish may be used to assess therapies, such as novel drug classes, which aim to boost REP activity.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available