Pediatr Nephrol (2011) 26:1181–1195 DOI 10.1007/s00467-010-1697-5 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 Introduction factor underlying the pathogenesis of both syndromic and isolated kidney cystic disease, an observation that has Cystic diseases of the kidney are a significant contributor to contributed to the unification of human genetic disorders of renal malformations and a common cause of end stage renal the cilium, the ciliopathies. Such grouping is underscored disease (ESRD). This classification encompasses a number by two major observations: the fact that genes encoding of human disorders that range from conditions in which ciliary proteins can contribute causal and modifying cyst formation is either the sole or the main clinical mutations across several clinically discrete ciliopathies, manifestation, to pleiotropic syndromes where cyst forma- and the emerging realization that an understanding of the tion is but one of the observed pathologies, exhibits clinical pathology of one ciliopathy can provide valuable variable penetrance, and can sometimes be undetectable insight into the pathomechanism of renal cyst formation until later in life or upon necropsy (Table 1;[1]). elsewhere in the ciliopathy spectrum. In this review, we Importantly, although the different cystic kidney disorders discuss and attempt to stratify the different lines of are clinically discrete entities, an extensive body of data proposed cilia-driven mechanisms for cystogenesis, ranging fueled by a combination of mutation identification in from mechano- and chemo-sensation, to cell shape and humans and studies in animal models suggests a common polarization, to the transduction of a variety of signaling thread, where virtually all known renal cystic disease- cascades. We evaluate both common trends and differences associated genes encode proteins necessary for aspects of across the models and discuss how each proposed mecha- ciliary function [2, 3]. Expanding from that observation, it nism can contribute to the development of novel therapeutic is now becoming apparent that most—if not all—disorders paradigms. of the cilium have a cystogenic component, which has in turn placed kidney cyst formation as a hallmark feature of Keywords Ciliopathies . Pleiotropic disorders . Disease the ciliopathies [4, 5]. modules . Paracrine signaling 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], their fundamental C. Gascue J. L. Badano organization is rigorously conserved and defined by a Institut Pasteur de Montevideo, microtubule core (axoneme) that is organized from a basal Mataojo 2020, Montevideo, CP 11400, Uruguay body, which is a structure composed of nine microtubule triplets derived from the mother centriole of the centro- N. Katsanis (*) some. Along this microtubule core, multiprotein complexes Center for Human Disease Modeling, and molecular motors are organized for transporting, both Duke University Medical Center, Box 3709, Durham, NC 27710, USA in (anterograde) and out (retrograde) of the cilium, the e-mail: [email protected] different components needed for the formation, mainte- 1182 Pediatr Nephrol (2011) 26:1181–1195 Table 1 Cystic diseases of the kidney: their causal genes, encoded proteins, localization, and proposed function Disease Main features Genes involved Corresponding protein Protein Postulated functions localization Autosomal Renal cyst, enlarged PKHD1 Fibrocystin/polyductin (FPC) Cilia and Calcium response; recessive PKD kidneys, hepatic fibrosis secreted proliferation/ (ARPKD) differentiation Autosomal Renal, hepatic, pancreatic PKD1, PKD2 Polycystin 1 (PC1) Polycystin Cilia, Golgi Calcium response; dominant PKD and brain cysts 2 (PC2) apparatus, proliferation/ (ADPKD) focal differentiation adhesions Nephronophthisis Renal fibrosis, renal cysts, NPHP1–NPHP11 Nephrocystin-1, 2/inversin, 3, Cilia, basal Cell–cell and cell–matrix (NPHP) and tubular atrophy, retinal 4, 5, 6/CEP290, 7/GLIS2, bodies, adhesion; actin Senior Løken dystrophy (in SNLS) 8/RPGRIP1L, 9/NEK8, centrosomes, cytoskeleton; cell Syndrome 11/Meckelin focal division; Wnt and Shh (SNLS) adhesions. signaling Joubert syndrome NPHP and cerebellar AHI1, NPHP1, CEP290, Jouberin, Nephrocystin, Cilia, basal Ciliogenesis, Sonic (JS) ataxia JBTS6/TMEM67, RPGRIP1L, CEP290, Meckelin, bodies, Hedgehog signaling ARL13B, CC2D2A, INPP5E, RPGRIP1L, ARL13B, centrosomes, JBTS2/TMEM216 CC2D2A, INPP5E, cell junctions TMEM216 Bardet–Biedl Renal cysts, obesity, BBS1-12, MKS1, CEP290, BBS1-12, MKS1, CEP290, Centrosomes, Pericentriolar organization, syndrome (BBS) polydactyly, retinal FRITZ, SDCCAG8 FRITZ, SDCCAG8 basal bodies ciliogenesis, Wnt dystrophy, mental signaling retardation Meckel–Gruber Occipital MKS1, MKS3/TMEM67, MKS1, meckelin, Centrosomes, Basal body localization, syndrome (MKS) meningoencephalocele, NPHP3, CEP290, nephrocystin 3, CEP290, cilia, ciliogenesis, Hedgehog cystic kidneys, liver RPGRIP1L, CC2D2A, MKS2/ RPGRIP1L, CC2D2A, plasma signaling fibrosis, polydactyly TMEM216 TMEM216 membrane Oral–facial–digital Malformations of face, oral OFD1 OFD1 Cilia, basal Ciliogenesis, L-R syndrome 1 cavity and digits, renal bodies, asymmetry, possibly (OFD1) cysts, polydactyly centrosomes, gene regulation nucleus Short-Rib Renal cysts, shortened DYN2CH1, IFT80 Cytoplasmic dynein 2 heavy Chondrocyte Intraflagelar transport, Polydactily bones, polydactyly, situs chain, IFT80 cilia, basal Hedgehog signaling (incl. Jeune inversus bodies Asphyxiating Thoracic Dystrophy) Uromodulin- Renal cysts, fibrosis, UMOD, MCKD1, MCKD2 Uromodulin Cilia, basal Unknown ciliary role associated kidney hypertension, bodies, diseases hypoeruricemia, centrosomes, (MCKD2, FJHN, secreted GCKD) PKD, Polycystic kidney disease; MCKD2, medullary cystic kidney disease type 2; FJHN, familial juvenile hyperuricemic nephropathy; GCKD, glomerulocystic kidney disease nance, and function of this complex organelle (Fig. 1). This interactions. Discoveries driven primarily by phenotypic process is known as intraflagellar transport (IFT) and was observations in both invertebrates and vertebrates (includ- described originally in the unicellular algae Chlamydomo- ing humans) have shown that primary cilia are important nas reinhardtii (for extensive reviews on the topic see, for for mechano- and chemo-sensation as well as for the signal example [7, 8]). Given its key role in maintaining ciliary transduction of short- and long-range paracrine signals, function, it is therefore not surprising that alterations in such as Wnt, Sonic Hedgehog (Shh), and platelet-derived different components of the IFT machinery have been growth factor receptor alpha (PDGFRα)[9–13]. Moreover, shown to cause the renal phenotype observed in different a number of additional receptors have been localized to human conditions and animal models of kidney cystic subsets of both sensory and motile cilia, suggesting that disease [4, 5, 9]. additional signaling mechanisms will likely be assigned to A flurry of observations during the past decade have these organelles. For example, it has been shown that the expanded our appreciation of cilia; transitioning from the somatostatin receptor type 3 (Sstr3) and the melanin- classical models of motile cilia and their necessity for fluid concentrating hormone receptor 1 (Mchr1) do localize to movement or cellular propulsion, we now recognize that cilia in neurons, thus providing an important insight into the primary, sensory cilia are critical for cell–environment feeding behavioral defects and obesity that characterize a Pediatr Nephrol (2011) 26:1181–1195 1183 Fig. 1 The cilium: basic struc- ture and function. Cilia are formed by a microtubule core (axoneme) that is organized from a basal body. Along the axoneme, intraflagellar transport (IFT) particles are transported in (anterograde) and out (retro- grade) of the cilium. The cilium concentrates and organizes a number of channels, receptors, and effectors, therefore playing a critical role in, for example, Ca2+ and paracrine signaling, ultimately regulating cellular, tissue, and organ homeostasis number of ciliopathies [14]. Consequently, our deeper lov-1,theclosestCaenorhabditis elegans homolog of understanding of the complex nature of this organelle is PKD1, localizes to primary cilia in sensory neurons in the contributing towards a better understanding of the mecha- nematode and by the characterization of the Oak Ridge nisms involved in the pathogenesis of ciliopathies, including polycystic kidney (orpk) mouse model of ARPKD, in the cystogenic process. In this review, we highlight how cilia which a hypomorphic mutation in Tg737 results in bilateral have been linked to a number of renal cystic disorders and polycystic kidneys and liver lesions [21, 22]. A key describe how our deeper understanding of the etiology of observation arose when Tg737, which encodes the protein this group of disorders is impacting their genetic dissection. termed polaris, was found to encode the mouse ortholog of Finally, we discuss how such knowledge might help the the Chlamydomonas IFT88, a protein