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Title: Zebrafish as model for human ciliopathies
Author: Leventea, Eleni
ISNI:       0000 0004 5992 2616
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2016
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Ciliopathies are a family of rare pleiotropic disorders associated with cilia defects. They display a wide variability of phenotypes but are also characterized by common manifestations. A typical example includes mutations in the CEP290 gene, which result in a widely variable severity of phenotypes ranging from retina disorders (e.g. Leber Congenital Amaurosis) to perinatal lethality (Meckel Gruber Syndrome). Aiming to characterise a wide spectrum of human ciliopathy phenotypes using the zebrafish model, we studied mutant alleles for bbs2 and bbs9, cep290, alms1, rab23 and tubby. In the course of this work, we sought to characterise the relevance of zebrafish mutant phenotypes to human manifestations of ciliopathy syndromes. Both bbs genes analysed exhibit skeletal morphogenesis defects during early juvenile stages, while only bbs9 but not bbs2 homozygous mutants are characterised by retinal degeneration. Cep290 homozygous mutants do not display obvious external defects, they are however characterised by high frequency of ectopic otoliths during larval stages, and hyperactivity both during larval and adult developmental stages. This behavioural defect led us to the observation of planar cell polarity and otolith crystal structural defects in one of the three ear chambers. Proteomic analysis additionally revealed differences between the protein content of cep290-/- mutant and non-mutant sibling otoliths, suggesting that Cep290 has a role in otolith biomineralisation. Alms1-/- mutants exhibit curly body axis, ciliogenesis defects and opsin mislocalization. Homozygous mutants are also characterised by cardiac defects. Lastly, rab23-/- mutants exhibit curly body axis, ciliogenesis and laterality defects while tub-/- are characterised by opsin trafficking defects in the retina. Collectively, this survey of zebrafish cilia mutants revealed new functions for genes involved in human ciliopathies. Zebrafish proved to be an excellent model to investigate these novel functions further.
Supervisor: Malicki, J. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available