Molecular mechanisms and phenotypic diversity in Bardet-Biedl syndrome

Ciliopathies are a group of rare diseases characterized by a wrong function or structure of the cilia. One of them is Bardet-Biedl syndrome, a multisystemic disease whose main symptoms are retinal degeneration, obesity, polydactyly, cognitive impairment, cryptorchidism and wrong renal structure and function, as well as other less common but of great clinical relevance symptoms such as liver fibrosis, diabetes and hypertension. Ciliopathies are a group of diseases characterized by an alteration in the function or structure of the primary cilium, a cellular organelle responsible for signal transduction. One of these diseases is Bardet-Biedl syndrome (BBS MIM # 209900), which is characterized by mutations in genes that code for a series of proteins that interact to form a protein complex, the BBSome. The precise molecular process underlying BBS manifestation remains unclear. The positioning and involvement of BBSome in ciliary signal transduction suggest a specific disruption of particular metabolic pathways. Nevertheless, the extensive phenotypic variability in this syndrome coincides with distinct tissue alterations, indicating that BBSome likely affects cell signalling through a shared mechanism influencing a majority of receptors within the cell. Numerous ciliopathies exhibit a pathological phenotype that significantly overlaps not only with other ciliopathies but also with different disease types. This is exemplified by BBS and mitochondrial diseases, where both entail multiple tissues and present symptoms such as optic atrophy, neurological involvement, and metabolic irregularities. Consequently, mitochondrial dysfunction could be viewed as a potential novel mechanism contributing to specific BBS symptoms. Building upon the aforementioned points, this thesis primarily aims to identify and elucidate common and fundamental cellular metabolic mechanisms that could account for the considerable phenotypic diversity observed in BBS.