%0 Thesis
%9 Doctoral
%A Tobin, J.
%B Molecular Medicine Unit
%D 2009
%F discovery:14468
%I UCL (University College London)
%P 315
%T A functional and therapeutic investigation of ciliopathy proteins and ciliopathies  
%U https://discovery.ucl.ac.uk/id/eprint/14468/
%X This thesis aims to investigate new functions for ciliopathy proteins and identify  candidates for therapeutic application. The ciliopathies form a class of genetic  diseases whose aetiology lies in the primary cilium. Over 30 genes have been  identified as mutant in ciliopathies and their proteins localise at the primary  cilium. When mutated they can cause kidney disease, obesity, polydactyly, and  retinal degeneration.  In this project, I have studied craniofacial dysmorphology related to Bardet-Biedl  syndrome (BBS) in humans, mice, and zebrafish, and shown there to be consistent  midfacial flattening and hypoplasia. Bbs8, a causative gene of BBS, has a key  role in neural crest migration and possibly in cell migration in general. This  accounts for the frequent observation of Hirschsprung’s disease, a gut immotility  disorder, in BBS. I identified new roles for BBS and other ciliopathy proteins in  Sonic hedgehog (Shh) signal transduction and showed that they are important in  the downstream processing of the transcription factor Gli3.  I modelled ten different ciliopathy genes in the zebrafish and identified specific  ciliary phenotypes, such as laterality randomisation, otic vesicle anomalies, and  kidney cysts. Administration of two drugs, Rapamycin and Roscovitine, were  sufficient to rescue formation of kidney cysts and restore the filterative capacity of  the kidney. This paves the way for studies in mouse models and, ultimately, in  humans, where no treatment for ciliopathic renal disease exists.  I examined whether FTO, a gene associated with obesity in the general  population, functioned in ciliary processes. I provided some evidence that its  protein was involved ciliary processes and glucose homeostasis. I also showed  that fto interacted with its neighbouring ciliary gene, ftm, in the zebrafish. I  performed similar interaction studies to show that a non-synonomous SNP in a  gene associated with lipid accumulation in C. elegans had deleterious effects on  protein function, explaining its high degree of association in BBS patients.