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Mutational and functional analyses of Bardet-Biedl syndrome

May-Simera, Helen Louise; (2008) Mutational and functional analyses of Bardet-Biedl syndrome. Doctoral thesis , UCL (University College London). Green open access

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This thesis investigates some of the underlying causes of Bardet-Biedl syndrome, a leading example of emerging ciliopathies. Bardet-Biedl syndrome (BBS) is a heterogeneous disorder with primary features that include age-related retinal dystrophy, obesity, Polydactyly, renal dysplasia, reproductive tract anomalies and cognitive impairment. To date 12 loci have been found to be causative for the disease (BBS1-12) and evidence suggests that aspects of the BBS phenotype may result from defective ciliogenesis/basal body function. The aims of this project were to identify new genes involved with the disease, analyse the phenotype of the Bbs6"7" mouse and further elucidate the mechanism of the disease in a zebrafish model. Pathogenic sequence mutations identified in candidate genes aided the identifictaion of BBS3 and BBS5. Further candidate genes were identified through the mapping of translocation breakpoints in a BBS patient. A yeast two-hybrid screen, using Bbs6 as bait, revealed several potential protein interactions. Phenotypical analysis of the Bbs&A mouse showed features comparable to BBS patients and other Bbs null mice, confirming its value as a model for further study. Further investigations of BBS proteins in the cochlea suggested a role beyond that of cilia and basal body function, namely that BBS proteins play distinct roles in the processes of microtubule nucleation and growth. Observed disruption of cochlear stereociliary bundles, along with other phenotypes associated with planar cell polarity (PCP) mutants, implied cilia might be involved in PCP signalling. This observation was supported by further analysis in the zebrafish. Disruption of bbs8 resulted in similar phenotypes to other PCP mutants, and laterality defects, thought to arise from defective cilia function at the Kupffer's Vesicle, were enhanced on a PCP mutant background. The results presented in this thesis pave the way for further investigation with a view to broadening the knowledge of the developmental processes behind BBS and also the processes behind the development of other signaling pathways, tissues and organ systems.

Type: Thesis (Doctoral)
Title: Mutational and functional analyses of Bardet-Biedl syndrome
Identifier: PQ ETD:591632
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest. Third party copyright material has been removed from the ethesis. Images identifying individuals have been redacted or partially redacted to protect their identity.
UCL classification: UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Child Health
URI: http://discovery.ucl.ac.uk/id/eprint/1444329
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