Cystic diseases of the kidney: ciliary dysfunction and cystogenic mechanisms
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REVIEW
Cystic diseases of the kidney: ciliary dysfunction and cystogenic mechanisms Cecilia Gascue & Nicholas Katsanis & Jose L. Badano
Received: 3 August 2010 / Revised: 15 September 2010 / Accepted: 15 October 2010 / Published online: 27 November 2010 # IPNA 2010
Abstract Ciliary dysfunction has emerged as a common factor underlying the pathogenesis of both syndromic and isolated kidney cystic disease, an observation that has contributed to the unification of human genetic disorders of the cilium, the ciliopathies. Such grouping is underscored by two major observations: the fact that genes encoding ciliary proteins can contribute causal and modifying mutations across several clinically discrete ciliopathies, and the emerging realization that an understanding of the clinical pathology of one ciliopathy can provide valuable insight into the pathomechanism of renal cyst formation elsewhere in the ciliopathy spectrum. In this review, we discuss and attempt to stratify the different lines of proposed cilia-driven mechanisms for cystogenesis, ranging from mechano- and chemo-sensation, to cell shape and polarization, to the transduction of a variety of signaling cascades. We evaluate both common trends and differences across the models and discuss how each proposed mechanism can contribute to the development of novel therapeutic paradigms. Keywords Ciliopathies . Pleiotropic disorders . Disease modules . Paracrine signaling
C. Gascue : J. L. Badano Institut Pasteur de Montevideo, Mataojo 2020, Montevideo, CP 11400, Uruguay N. Katsanis (*) Center for Human Disease Modeling, Duke University Medical Center, Box 3709, Durham, NC 27710, USA e-mail: [email protected]
Introduction Cystic diseases of the kidney are a significant contributor to renal malformations and a common cause of end stage renal disease (ESRD). This classification encompasses a number of human disorders that range from conditions in which cyst formation is either the sole or the main clinical manifestation, to pleiotropic syndromes where cyst formation is but one of the observed pathologies, exhibits variable penetrance, and can sometimes be undetectable until later in life or upon necropsy (Table 1; [1]). Importantly, although the different cystic kidney disorders are clinically discrete entities, an extensive body of data fueled by a combination of mutation identification in humans and studies in animal models suggests a common thread, where virtually all known renal cystic diseaseassociated genes encode proteins necessary for aspects of ciliary function [2, 3]. Expanding from that observation, it is now becoming apparent that most—if not all—disorders of the cilium have a cystogenic component, which has in turn placed kidney cyst formation as a hallmark feature of the ciliopathies [4, 5]. Primary cilia, motile cilia, and flagella are evolutionary conserved organelles that extend from the apical plasma membrane. Although cilia and flagella do demonstrate underappreciated structural and architectural diversity across phyla and tissue types [6],
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