Renal Ciliopathies


Defects in centrosome and cilium function lead to phenotypically related syndromes called ciliopathies. Cilia are microtubule‐based antennae that detect and orchestrate extracellular stimuli. As environmental rheostats and cellular signalling centres, they mediate multiple pathways that if disrupted lead to early developmental defects and cancer. Cystic kidney disorders such as polycystic kidney disease (ADPKD/ARPKD) and nephronophthisis (NPHP) play a central role in the elucidation of ciliopathies, and practically, all cilia‐related disorders can show renal cysts. In addition, patients may present with extrarenal manifestations in other organs. An accurate genetic diagnosis is crucial for genetic counselling, prenatal diagnostics and the clinical management of patients and their families. The increasing number of genes that have to be considered in patients with ciliopathies is challenging to address by conventional techniques and largely benefits from next‐generation sequencing (NGS)‐based approaches.

Key Concepts

  • Polycystic kidney disease (PKD) constitutes the most common life‐threatening genetic disorder and affects about 10–15 million people worldwide.
  • The majority of patients with PKD harbour mutations in the typical genes for ARPKD and ADPKD; however, mutations in other genes can mimic PKD.
  • PKD paved the way for other cilia‐related disorders of which most can show renal cysts.
  • Renal ciliopathies are characterized by tremendous clinical and genetic heterogeneity.
  • Patients may present with extrarenal manifestations in other organs (e.g. liver cysts, heart defects, retinal degeneration, deafness and intracranial aneurysms).
  • The underlying genotype can usually be identified by next‐generation sequencing (NGS)‐based approaches that allow the parallel analysis of all disease genes.
  • An accurate genetic diagnosis is crucial for genetic counselling, prenatal diagnostics and clinical management (with early detection and treatment of complications).

Keywords: cilia/ciliopathies; cystic kidneys; polycystic kidney disease (ADPKD/ARPKD); nephronophthisis (NPHP); Meckel syndrome (MKS); Joubert syndrome (JBTS); Bardet–Biedl syndrome (BBS); Alstrom syndrome; short‐rib polydactyly syndromes; Jeune syndrome (ATD)

Figure 1. Schematic diagram of a primary cilium and associated processes. Polycystic kidney disease is controlled by a defined network of different genes/proteins discussed in this article. Cilia are small antennae that detect a variety of different extracellular stimuli and orchestrate multiple signalling pathways with nuclear trafficking of some molecules (e.g. C‐termini of polycystin‐1 (PC1) and fibrocystin/polyductin (FPC)). The inner ciliary structure is defined by the axoneme composed of nine microtubule doublets derived from the basal body and mother centriole of the centrosome. Along this microtubule core, the (anterograde) transport of proteins towards the tip of the cilium and in the retrograde direction towards the cell body is organized by an elaborate process called intraflagellar transport (IFT).
Figure 2. Organs frequently affected in cilia‐related disorders.
Figure 3. (a–g) Broad clinical spectrum of ciliopathies ranging from single‐organ involvement to complex, early embryonic disorders in which multiple organs can be affected.
Figure 4. (a, c) Macroscopic appearance of advanced‐stage ADPKD showing enlarged kidneys with multiple cysts that almost completely destructed and replaced the renal parenchyma. (b) On cut section, multiple cysts in the cortex and medulla can be seen that vary considerably in size and appearance, from a few millimetres to diameters of many centimetres. Reproduced with permission from Bergmann, Pediatr Nephrol 2014 © Springer.
Figure 5. Autosomal recessive polycystic kidney disease (ARPKD). (a) Baby with distended abdomen due to voluminous kidneys that lead to respiratory problems. (b) Abdominal situs of a perinatally demised ARPKD patient with symmetrically enlarged kidneys that maintain their reniform configuration. (c) Potter's phenotype with distinctive facial features due to lack of amniotic fluid. (d–h) Renal ultrasound of babies and young children with ARPKD. Symmetrically enlarged echogenic kidneys with fusiform dilations of collecting ducts and distal tubules arranged radially throughout the renal parenchyma from medulla to cortex. Reproduced with permission from Bergmann, Pediatr Nephrol 2014 © Springer.


AbouAlaiwi WA, Ratnam S, Booth RL, Shah JV and Nauli SM (2011) Endothelial cells from humans and mice with polycystic kidney disease are characterized by polyploidy and chromosome segregation defects through survivin down‐regulation. Human Molecular Genetics 20: 354–367.

Adeva M, El‐Youssef M and Rossetti S (2006) Clinical and molecular characterization defines a broadened spectrum of autosomal recessive polycystic kidney disease (ARPKD). Medicine (Baltimore) 85: 1–21.

Avni FE, Guissard G, Hall M, et al. (2002) Hereditary polycystic kidney diseases in children: changing sonographic patterns through childhood. Pediatric Radiology 32: 169–174.

Bae KT, Zhu F, Chapman AB, et al. (2006) Magnetic resonance imaging evaluation of hepatic cysts in early autosomal‐dominant polycystic kidney disease: the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease cohort. Clinical Journal of the American Society of Nephrology 1: 64–69.

Battini L, Macip S, Fedorova E, et al. (2008) Loss of polycystin‐1 causes centrosome amplification and genomic instability. Human Molecular Genetics 17: 2819–2833.

Baujat G and Le Merrer M (2007) Ellis‐van Creveld syndrome. Orphanet Journal of Rare Diseases 2: 27.

Bergmann C (2012) Educational paper: Ciliopathies. European Journal of Pediatrics 171: 1285–1300.

Bergmann C (2014) ARPKD and early manifestations of ADPKD: the original polycystic kidney disease and phenocopies. Pediatric Nephrology 30 (1): 15–30 [Epub ahead of print].

Bergmann C, Fliegauf M, Bruchle NO, et al. (2008) Loss of nephrocystin‐3 function can cause embryonic lethality, Meckel‐Gruber‐like syndrome, situs inversus, and renal‐hepatic‐pancreatic dysplasia. American Journal of Human Genetics 82: 959–970.

Bergmann C, Senderek J, Windelen E, et al. (2005) Clinical consequences of PKHD1 mutations in 164 patients with autosomal‐recessive polycystic kidney disease (ARPKD). Kidney International 67: 829–848.

Bergmann C, von Bothmer J, Ortiz Brüchle N, et al. (2011) Mutations in multiple PKD genes may explain early and severe polycystic kidney disease. Journal of the American Society of Nephrology 22: 2047–2056.

Cornec‐Le Gall E, Audrézet M‐P, Chen J‐M, et al. (2013) Type of PKD1 mutation influences renal outcome in ADPKD. Journal of the American Society of Nephrology 24: 1006–1013.

Crino PB, Nathanson KL and Henske EP (2006) The tuberous sclerosis complex. New England Journal of Medicine 355: 1345–1356.

Desmet VJ (1998) Ludwig symposium on biliary disorders—part I. Pathogenesis of ductal plate abnormalities. Mayo Clinic Proceedings 73: 80–89.

Drenth JP, Chrispijn M and Bergmann C (2010) Congenital fibrocystic liver diseases. Best Practice & Research Clinical Gastroenterology 24: 573–584.

Fedeles SV, Tian X, Gallagher A‐R, et al. (2011) A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin‐1 as the central determinant of cyst formation. Nature Genetics 43: 639–647.

Follit JA, Li L, Vucica Y and Pazour GJ (2010) The cytoplasmic tail of fibrocystin contains a ciliary targeting sequence. Journal of Cell Biology 188: 21–28.

Forsythe E and Beales PL (2013) Bardet‐Biedl syndrome. European Journal of Human Genetics 21: 8–13.

Gerdes JM, Davis EE and Katsanis N (2009) The vertebrate primary cilium in development, homeostasis, and disease. Cell 137: 32–45.

Goetz SC and Anderson KV (2010) The primary cilium: a signalling centre during vertebrate development. Nature Reviews Genetics 11: 331–344.

Grantham JJ (1990) Polycystic kidney disease: neoplasia in disguise. American Journal of Kidney Diseases 15: 110–116.

Guay‐Woodford LM and Desmond RA (2003) Autosomal recessive polycystic kidney disease: the clinical experience in North America. Pediatrics 111: 1072–1080.

Gunay‐Aygun M, Font‐Montgomery E, Lukose L, et al. (2013) Characteristics of congenital hepatic fibrosis in a large cohort of patients with autosomal recessive polycystic kidney disease. Gastroenterology 144: 112–121, e112.

Han YG, Kim HJ, Dlugosz AA, et al. (2009) Dual and opposing roles of primary cilia in medulloblastoma development. Nature Medicine 15: 1062–1065.

Harris PC, Bae KT, Rossetti S, et al. (2006) Cyst number but not the rate of cystic growth is associated with the mutated gene in autosomal dominant polycystic kidney disease. Journal of the American Society of Nephrology: JASN 17: 3013–3019.

Harris PC and Torres VE (2006) Understanding pathogenic mechanisms in polycystic kidney disease provides clues for therapy. Current Opinion in Nephrology and Hypertension 15 (4): 456–463.

Harris PC and Torres VE (2009) Polycystic kidney disease. Annual Review of Medicine 60: 321–337.

Hildebrandt F, Benzing T and Katsanis N (2011) Ciliopathies. New England Journal of Medicine 364: 1533–1543.

Hoff S, Halbritter J, Epting D, et al. (2013) ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3. Nature Genetics 45: 951–956.

Kaelin WG Jr (2008) The von Hippel‐Lindau tumour suppressor protein: O2 sensing and cancer. Nature Reviews Cancer 8: 865–873.

Kim I, Fu Y, Hui K, et al. (2008) Fibrocystin/polyductin modulates renal tubular formation by regulating polycystin‐2 expression and function. Journal of the American Society of Nephrology 19: 455–468.

Kirby A, Gnirke A, Jaffe DB, et al. (2013) Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing. Nature Genetics 45: 299–303.

Martin‐Belmonte F and Perez‐Moreno M (2012) Epithelial cell polarity, stem cells and cancer. Nature Reviews Cancer 12: 23–38.

Masyuk TV, Huang BQ, Ward CJ, et al. (2003) Defects in cholangiocyte fibrocystin expression and ciliary structure in the PCK rat. Gastroenterology 125: 1303–1310.

Moser M, Matthiesen S, Kirfel J, et al. (2005) A mouse model for cystic biliary dysgenesis in autosomal recessive polycystic kidney disease (ARPKD). Hepatology 41: 1113–1121.

Nigg EA and Raff JW (2009) Centrioles, centrosomes, and cilia in health and disease. Cell 139 (4): 663–678.

Onuchic LF, Furu L, Nagasawa Y, et al. (2002) PKHD1, the polycystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple immunoglobulin‐like plexin‐transcription‐factor domains and parallel beta‐helix 1 repeats. American Journal of Human Genetics 70: 1305–1317.

Parisi MA (2009) Clinical and molecular features of Joubert syndrome and related disorders. American Journal of Medical Genetics Part C: Seminars in Medical Genetics 151C: 326–340.

Poliseno L, Salmena L, Zhang J, et al. (2010) A coding‐independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 465: 1033–1038.

Rossetti S, Torra R, Coto E, et al. (2003) A complete mutation screen of PKHD1 in autosomal‐recessive polycystic kidney disease (ARPKD) pedigrees. Kidney International 64: 391–403.

Salomon R, Saunier S and Niaudet P (2009) Nephronophthisis. Pediatric Nephrology 24: 2333–2344.

Salonen R, Kestila M and Bergmann C (2011) Clinical utility gene card for: Meckel syndrome. European Journal of Human Genetics 19 (7).

Schmidts M, Arts HH, Bongers EM, et al. (2013) Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement. Journal of Medical Genetics 50: 309–323.

Shepherd CW, Gomez MR, Lie JT and Crowson CS (1991) Causes of death in patients with tuberous sclerosis. Mayo Clinic Proceedings 66: 792–796.

Shillingford JM, Murcia NS, Larson CH, et al. (2006) The mTOR pathway is regulated by polycystin‐1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proceedings of the National Academy of Sciences of the United States of America 103: 5466–5471.

Torres VE and Harris PC (2009) Autosomal dominant polycystic kidney disease: the last 3 years. Kidney International 76: 149–168.

Torres VE, Harris PC and Pirson Y (2007) Autosomal dominant polycystic kidney disease. Lancet 369: 1287–1301.

Turkbey B, Ocak I and Daryanani K (2009) Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis (ARPKD/CHF). Pediatric Radiology 39: 100–111.

Vylet'al P, Kublova M, Kalbacova M, et al. (2006) Alterations of uromodulin biology: a common denominator of the genetically heterogeneous FJHN/MCKD syndrome. Kidney International 70: 1155–1169.

Wang S, Zhang J, Nauli SM, et al. (2007) Fibrocystin/polyductin, found in the same protein complex with polycystin‐2, regulates calcium responses in kidney epithelia. Molecular and Cellular Biology 27: 3241–3252.

Ward CJ, Hogan MC, Rossetti S, et al. (2002) The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor‐like protein. Nature Genetics 30: 259–269.

Weaver BA and Cleveland DW (2008) The aneuploidy paradox in cell growth and tumorigenesis. Cancer Cell 14: 431–433.

Wong SY, Seol AD, So PL, et al. (2009) Primary cilia can both mediate and suppress Hedgehog pathway‐dependent tumorigenesis. Nature Medicine 15: 1055–1061.

Wu Y, Dai X‐Q, Li Q, et al. (2006) Kinesin‐2 mediates physical and functional interactions between polycystin‐2 and fibrocystin. Human Molecular Genetics 15: 3280–3292.

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Bergmann, Carsten(Jan 2015) Renal Ciliopathies. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025223]