Abstract
Cilia are microtubule-based organelles, protruding from the apical cell surface and anchoring to the cytoskeleton. Primary (nonmotile) cilia of the kidney act as mechanosensors of nephron cells, responding to fluid movements by triggering signal transduction. The impaired functioning of primary cilia leads to formation of cysts which in turn contribute to development of diverse renal diseases, including kidney ciliopathies and renal cancer. Here, we review current knowledge on the role of ciliary genes in kidney ciliopathies and renal cell carcinoma (RCC). Special focus is given on the impact of mutations and altered expression of ciliary genes (e.g., encoding polycystins, nephrocystins, Bardet-Biedl syndrome (BBS) proteins, ALS1, Oral-facial-digital syndrome 1 (OFD1) and others) in polycystic kidney disease and nephronophthisis, as well as rare genetic disorders, including syndromes of Joubert, Meckel-Gruber, Bardet-Biedl, Senior-Loken, Alström, Orofaciodigital syndrome type I and cranioectodermal dysplasia. We also show that RCC and classic kidney ciliopathies share commonly disturbed genes affecting cilia function, including VHL (von Hippel-Lindau tumor suppressor), PKD1 (polycystin 1, transient receptor potential channel interacting) and PKD2 (polycystin 2, transient receptor potential cation channel). Finally, we discuss the significance of ciliary genes as diagnostic and prognostic markers, as well as therapeutic targets in ciliopathies and cancer.
Highlights
Cilia are microtubule-based organelles, protruding from the apical cell surface and anchoring to the cytoskeleton
It was suggested that VHL-loss induces formation of renal cysts which are precursor lesions that progress to clear cell renal cell carcinoma in patients with von Hippel-Lindau disease [151]
According to the unifying theory of renal cystogenesis, ciliopathies are caused by mutations in genes encoding proteins expressed in primary cilia, basal bodies and centrosomes which affect cilia functioning, thereby contributing to disturbed cilia-controlled signaling pathways
Summary
Discovered almost coincidentally in 1676 by Anton van Leeuwenhoek, cilia have been ignored by the scientific community until the 20th century when electron microscopy and immunocytochemistry techniques allowed the fine description of the ciliary structure and composition [1,2]. Primary cilia act as sensory organs involved in transmission of signals from the extracellular environment into cells, by triggering crucial signaling pathways including Wnt, Planar Cell Polarity (PCP) and Hedgehog pathways [6] They detect different stimuli such as fluid shear, mechanic deformation (movement, vibration, touch), light or odorants. Structural or functional impairments of primary cilia caused by mutations in ciliary genes lead to dysregulation of signals transduction or inability to response to stimuli. Single cilium is composed of hundreds proteins responsible for their proper structure and function These ciliary proteins contribute to the cellular response to signals from different pathways, including the Hedgehog, Planar Cell Polarity (PCP), Platelet-derived growth factor (PDGF), fibroblast growth factor (FGF) and VHL/GSK3β (the von Hippel–Lindau tumor suppressor/Glycogen synthase kinase 3 beta) pathways [6,21]. We discuss the kidney ciliopathies by characterizing the ciliary genes involved in their pathology
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