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R. Roepman, J. van Reeuwijk, K. Boldt, M. Ueffing; A Network Approach to Dissect the Molecular Disease Mechanisms of Retinal Ciliopathies. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3738.
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© ARVO (1962-2015); The Authors (2016-present)
Cilia are centriole-derived, finger-like projections from the cell surface that have a crucial function in transducing extracellular signals and regulating many biological processes. Developmentally, the photoreceptor outer sements are highly specialized sensory cilia. At their base, they contain a microtubule-based axoneme and basal body that connects to the inner segment at the ciliary transition zone or photoreceptor connecting cilium. Inherited defects in various proteins that localize to this cilium are among the most frequent causes of retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA). Importantly, ciliary dysfunction is involved in two dozen disorders with different phenotypes that often include retinal degeneration, the "ciliopathies". We have initiated a functional genomics-based approach to gain insight into the (disrupted) ciliary protein networks and signalling pathways that are associated with photoreceptor cilium dysfunction in retinal ciliopathies.
Data from optimized yeast two-hybrid screens (Y2H), Tandem Affinity Purification (SF-TAP), and Stable Isotope Labelling with Amino acids in Cell culture (SILAC) experiments were annotated in a relational, updatable MySQL database, together with data from the public domain, e.g. UniProt annotation, Entrez Gene Interactions (HPRD, BioGRID, BIND), HomoMINT interactions, and the Ciliary Proteome Database (www.ciliaproteome.org). Queries were performed using multiple parameters, and results were used to dissect the (connecting) ciliary functional modules.
We have constructed an integrated map of the ciliary interactome associated with key proteins involved in retinal ciliopathies, such as RPGR, RPGRIP1, nephrocystin-4, USH2A and lebercilin. Our data indicate an overrepresentation of lebercilin and RPGRIP1 interacting proteins that are linked to cilia related functions, which also validates the approach we have taken.
Most of the proteins involved in retinal ciliopathies are either direct or indirect (2nd neighbor) interaction partners of each other, and link the disease proteins to a possible role in important signaling pathways such as Wnt/PCP, and Shh. By inclusion of genetic linkage analysis data of patients with a genetically unsolved ciliopathy, our data may also be used to identify "candidate ciliopathy genes".
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