Technological advances have hyper-accelerated gene discovery and hold great promise of bringing genomic technologies to the clinic as a first-stage diagnostic tool. However, many challenges remain to reach that goal, including the fact that variable penetrance and expressivity are highly prevalent, even in traditional monogenic traits and that our understanding of the genetic mechanisms that contribute to phenotypic variability remain largely elusive. Bardet-Biedl syndrome (BBS) has served as a useful model for understanding genetic architecture and for dissecting second-site modification in humans. As part of our long-standing investigations, we have identified a significant fraction of causal BBS genes, we have interrogated the nature of second-site modification and we have developed in vivo tools to dissect the effect of variants on the phenotype and model epistasis. Further, we have unified BBS and other clinically-overlapping disorders under the ciliopathy umbrella and have shown that the distribution and nature of dysfunction in the primary cilium and its anchoring structure, the basal body, can inform disease causality and severity. Our competing renewal is composed of three Aims. First, saturated nextgen sequencing of the ciliary proteome, as well as more traditional studies, have identified primary mutations in ~80% of BBS patients. We propose to use whole exome sequencing in families bereft of causal ciliary mutations to identify novel BBS genes. Second, our preliminary data suggest that CNVs are a major contributor to the mutational burden of BBS and other ciliopathies. As such, we will use a custom-designed CGH array with ultra-high density across the ciliary proteome to systematically identify the CNV burden in these disorders and to uncover both causal and potential epistatic interactions. Finally, we have significant new data that implicate the proteasome as a protagonist for the diverse signaling defects observed in BBS animal models and patients. We will therefore ask whether pharmacological agonists of proteasomal activity are of therapeutic benefit to BBS animal models by assessing whether administration of such compounds to mouse BBS models can improve phenotypic outcomes in key sites of pathology. Taken together, our studies will a) illuminate new pathogenic mechanisms orthogonal to the ciliary disease paradigms;b) enrich our understanding on the contribution of CNVs in ciliopathies, and inform genetic architecture;and c) provide the first therapeutic lead that, if successful, would b suitable for clinical trials.
Our studies will identify new BBS genes that are not known or predicted to be associated with the cilium or the basal body, thereby providing orthogonal insight into the causality of the disease and the biology of this fascinating organelle. Further, fr the first time we will interrogate at high resolution the contribution of CNVs in this disorder and together with our previously established data on the nature and distribution of point mutations across the ciliary proteome, we will compile a comprehensive picture of mutational distribution that informs both causality and second-site modification. Finally, fuelled by biochemical studies in BBS models and patients, we will ask whether pharmacological amelioration of proteasomal function is of potential therapeutic benefit to BBS patients;given that some of these compounds are already approved by the FDA, these studies could facilitate the initiation of the first clinica trials not only for BBs patients, but also for patients with other related ciliopathies.
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