Hoskins, B.E.; (2005) The molecular and functional genetics of Bardet-Biedl Syndrome. Doctoral thesis , University of London.

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Abstract

Bardet-Biedl Syndrome (BBS) is a rare genetic disease comprising obesity, retinal dystrophy, Polydactyly and renal abnormalities. When this study began there were six known loci for BBS, only one of which, BBS6, had been identified. The initial aims of the project were to find BBS genes by screening of candidate genes within the known intervals and performing a genome wide screen using previously unlinked patients. During the time of this project three of the known BBS loci {lcub}BBSI, 2 and 4) have been identified and a further two novel genes (BBS7 and 8) have also been cloned. BBS was previously thought to be a recessive disease, but through mutation screening of all BBS genes in our cohort of 160 patients we have found evidence for complex inheritance involving the requirement for three mutations a homozygous mutation in one BBS gene and a further heterozygous mutation at a second BBS locus, to manifest disease in some families. As a quick and cheap alternative to sequencing for mutation detection, I developed the technique of multiplex capillary heteroduplex analysis (MCHA) which is now in routine use for screening new BBS cases. To determine the possible function of the BBS4 protein, a yeast-two-hybrid screen was undertaken to identify interactors of BBS4. Pericentriolar Material 1 (PCM1), one of the potential interactors, also co-localises with the protein at the centriolar satellites of centrosomes and basal bodies of primary cilia. The BBS8 protein, which shares homology with BBS4 also localises to the basal body and, from immunohistochemistry experiments using the BBS8 antibody, has been shown to be expressed in ciliated tissues such as kidney, retina, brain and spermatids, implicating basal body dysfunction in the aetiology of BBS. During the course of my studies, we have progressed from a handful of genetic loci to the determination of the putative protein function which may pave the way to the design of future therapies.

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