Polycystic kidney disease: The cilium as a common pathway in cystogenesis

Current Opinion in Pediatrics

Volumn 16, Issue 2, 2004, Pages 171-176

  Lin, Fangming ^a   Satlin, Lisa M ^b  

^a UNIVERSITY OF TEXAS AT DALLAS   (United States)

^b MOUNT SINAI SCHOOL OF MEDICINE   (United States)

Author keywords

Cilia; Cystogenesis; Polycystic kidney disease

Indexed keywords

CHEMORECEPTOR; CLINICAL FEATURE; EUKARYOTIC FLAGELLUM; GENETIC ASSOCIATION; GENETIC CORRELATION; HUMAN; KIDNEY CYST; KIDNEY POLYCYSTIC DISEASE; MECHANORECEPTOR; MICROENVIRONMENT; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION;

HUMANS; POLYCYSTIC KIDNEY DISEASES;

EID: 1642294210     PISSN: 10408703     EISSN: None     Source Type: Journal    
DOI: 10.1097/00008480-200404000-00010     Document Type: Review

References (68)

1. Igarashi P, Somlo S: Genetics and pathogenesis of polycystic kidney disease. J Am Soc Nephrol 2002, 13:2384-2398. An excellent and comprehensive review of the clinical presentation, genetics, and pathogenesis of ADPKD and ARPKD. The importance of cilia in cyst formation is discussed. Several animal models of PKD are introduced in this review.
2. Blyth H, Ockenden BG: Polycystic disease of kidney and liver presenting in childhood. J Med Genet 1971, 8:257-284.
3. Kaplan BS, Kaplan P, de Chadarevian JP, et al.: Variable expression of autosomal recessive polycystic kidney disease and congenital hepatic fibrosis within a family. Am J Med Genet 1988, 29:639-647.
4. Kaplan BS, Fay J, Shah V, et al.: Autosomal recessive polycystic kidney disease. Pediatr Nephrol 1989, 3:43-49.
5. Guay-Woodford LM, Desmond RA: Autosomal recessive polycystic kidney disease: the clinical experience in North America. Pediatrics 2003, 111: 1072-1080.
6. Zerres K, Mucher G, Becker J, et al.: Prenatal diagnosis of autosomal recessive polycystic kidney disease (ARPKD): molecular genetics, clinical experience, and fetal morphology. Am J Med Genet 1998, 76:137-144.
7. Hateboer N, v Dijk MA, Bogdanova N, et al.: Comparison of phenotypes of polycystic kidney disease types 1 and 2. European PKD1-PKD2 Study Group. Lancet 1999, 353:103-107.
8. Torra R, Badenas C, Perez-Oller L, et al.: Increased prevalence of polycystic kidney disease type 2 among elderly polycystic patients. Am J Kidney Dis 2000, 36:728-734.
9. Fick GM, Johnson AM, Strain JD, et al.: Characteristics of very early onset autosomal dominant polycystic kidney disease. J Am Soc Nephrol 1993, 3:1863-1870.
10. Fick GM, Duley IT, Johnson AM, et al.: The spectrum of autosomal dominant polycystic kidney disease in children. J Am Soc Nephrol 1994, 4:1654-1660.
11. Gabow PA, Grantham JJ: Polycystic Kidney Disease. Edited by Schrier RW, Gottschalk CW. Boston: Little Brown; 1997.
12. Kaariainen H, Koskimies O, Norio R: Dominant and recessive polycystic kidney disease in children: evaluation of clinical features and laboratory data. Pediatr Nephrol 1988, 2:296-302.
13. Kaariainen H, Jaaskelainen J, Kivisaari L, et al.: Dominant and recessive polycystic kidney disease in children: classification by intravenous pyelography, ultrasound, and computed tomography. Pediatr Radiol 1988, 18:45-50.
14. Potter E: Facial characteristics of infants with bilateral renal agenesis. Am J Obstet Gynecol 1946, 51:885-888.
15. Lieberman E, Salinas-Madrigal L, Gwinn JL, et al.: Infantile polycystic disease of the kidneys and liver: clinical, pathological and radiological correlations and comparison with congenital hepatic fibrosis. Medicine (Baltimore) 1971, 50:277-318.
16. Gagnadoux MF, Habib R, Levy M, et al.: Cystic renal diseases in children. Adv Nephrol Necker Hosp 1989, 18:33-57.
17. Cole BR, Conley SB, Stapleton FB: Polycystic kidney disease in the first year of life. J Pediatr 1987, 111:693-699.
18. Guay-Woodford LM, Muecher G, Hopkins SD, et al.: The severe perinatal form of autosomal recessive polycystic kidney disease maps to chromosome 6p21.1-p12: implications for genetic counseling. Am J Hum Genet 1995, 56:1101-1107.
19. Anand SK, Chan JC, Lieberman E: Polycystic disease and hepatic fibrosis in children. Renal function studies. Am J Dis Child 1975, 129:810-813.
20. Iglesias CG, Torres VE, Offord KP, et al.: Epidemiology of adult polycystic kidney disease, Olmsted County, Minnesota: 1935-1980. Am J Kidney Dis 1983, 2:630-639.
21. Bear JC, McManamon P, Morgan J, et al.: Age at clinical onset and at ultrasonographic detection of adult polycystic kidney disease: data for genetic counselling. Am J Med Genet 1984, 18:45-53.
22. Sedman A, Bell P, Manco-Johnson M, et al.: Autosomal dominant polycystic kidney disease in childhood: a longitudinal study. Kidney Int 1987, 31:1000-1005.
23. Milutinovic J, Schabel SI, Ainsworth SK: Autosomal dominant polycystic kidney disease with liver and pancreatic involvement in early childhood. Am J Kidney Dis 1989, 13:340-344.
24. Proesmans W, Van Damme B, Casaer P, et al.: Autosomal dominant polycystic kidney disease in the neonatal period: association with a cerebral arteriovenous malformation. Pediatrics 1982, 70:971-975.
25. Nadasdy T, Laszik Z, Lajoie G, et al.: Proliferative activity of cyst epithelium in human renal cystic diseases. J Am Soc Nephrol 1995, 5:1462-1468.
26. Grantham JJ: 1992 Homer Smith Award. Fluid secretion, cellular proliferation, and the pathogenesis of renal epithelial cysts. J Am Soc Nephrol 1993, 3: 1841-1857.
27. Wilson PD, Sherwood AC, Palla K, et al.: Reversed polarity of Na(+)-K(+)-ATPase: mislocation to apical plasma membranes in polycystic kidney disease epithelia. Am J Physiol 1991, 260:F420-F430.
28. Murcia NS, Sweeney WE Jr, Avner ED: New insights into the molecular pathophysiology of polycystic kidney disease. Kidney Int 1999, 55:1187-1197.
29. Calvet JP: Polycystic kidney disease: primary extracellular matrix abnormality or defective cellular differentiation? Kidney Int 1993, 43:101-108.
30. Ward CJ, Hogan MC, Rossetti S, et al.: The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein. Nat Genet 2002, 30:259-269. Taking the approach of mapping the syntenic region on chromosome 9 of the Pck rat model of ARPKD, the authors identified PKHD1, the human ARPKD gene, on chromosome 6. Mutational analyses were performed in pck rats and in humans with ARPKD. The protein product of PKHD1 was named fibrocystin. This group of investigators was one of the first to clone the PKHD1 gene in 2002.
31. Onuchic LF, Furu L, Nagasawa Y, et al.: 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. Am J Hum Genet 2002, 70:1305-1317. This is the second group that independently cloned PKHD1 in 2002. The authors assembled the transcription map of the human ARPKD region and identified a transcript that is highly expressed in the kidney. Mutations were detected in patients with ARPKD. The protein product was named polyductin.
32. Xiong H, Chen Y, Yi Y, et al.: A novel gene encoding a TIG multiple domain protein is a positional candidate for autosomal recessive polycystic kidney disease. Genomics 2002, 80:96-104. The third group to identify the PKHD1 in 2002 using a positional cloning and sequencing approach. The authors also mapped the mouse ortholog to mouse chromosome 1.
33. Rossetti S, Torra R, Coto E, et al.: A complete mutation screen of PKHD1 in autosomal-recessive polycystic kidney disease (ARPKD) pedigrees. Kidney Int 2003, 64:391-403. The authors developed the method for rapid mutation analysis in humans with ARPKD using denaturing high-performance liquid chromatography (DHPLC) to detect base pair changes. The rate of mutation detection was correlated with the severity of the disease.
34. Peters DJ, Sandkuijl LA: Genetic heterogeneity of polycystic kidney disease in Europe. Contrib Nephrol 1992, 97:128-139.
35. Kimberling WJ, Fain PR, Kenyon JB, et al.: Linkage heterogeneity of autosomal dominant polycystic kidney disease. N Engl J Med 1988, 319:913-918.
36. The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. The European Polycystic Kidney Disease Consortium. Cell 1994, 77:881-894.
37. Hughes J, Ward CJ, Peral B, et al.: The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains. Nat Genet 1995, 10:151-160.
38. Rossetti S, Strmecki L, Gamble V, et al.: Mutation analysis of the entire PKD1 gene: genetic and diagnostic implications. Am J Hum Genet 2001, 68: 46-63.
39. Rossetti S, Burton S, Strmecki L, et al.: The position of the polycystic kidney disease 1 (PKD1) gene mutation correlates with the severity of renal disease. J Am Soc Nephrol 2002, 13:1230-1237. The authors analyzed 80 families with PKD1 mutations and found no clear correlation between genotype (type of mutation in the PKD1 gene) and the phenotype (presentation of the disease). However, mutations at the 5′ region appeared to have early onset of end-stage renal disease and have more severe disease presentation.
40. Mochizuki T, Wu G, Hayashi T, et al.: PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 1996, 272: 1339-1342.
41. Wheatley DN: Primary cilia in normal and pathological tissues. Pathobiology 1995, 63:222-238.
42. McGrath J, Somlo S, Makova S, et al.: Two populations of node monocilia initiate left-right asymmetry in the mouse. Cell 2003, 114:61-73. In this elegant study using mice expressing a GFP-tagged left-right dynein fusion protein, two populations of cilia were identified in embryonic nodes. The authors provide evidence to show that coordination of the central motile cilia and the peripheral immotile cilia in embryonic node determines left-right axis formation.
43. Zimmerman K: Beitrage Zur kenntnis einiger Drusen und Epithelien. Arch Mikrosk Anat 1898, 52:552-706.
44. Pazour GJ, Witman GB: The vertebrate primary cilium is a sensory organelle. Curr Opin Cell Biol2003, 15:105-110. This is a concise review of the structure and function of primary cilia The role of cilia in polycystic kidney disease is discussed.
45. Moyer JH, Lee-Tischler MJ, Kwon HY, et al.: Candidate gene associated with a mutation causing recessive polycystic kidney disease in mice. Science 1994, 264:1329-1333.
46. Murcia NS, Richards WG, Yoder BK, et al.: The Oak Ridge Polycystic Kidney (orpk) disease gene is required for left-right axis determination. Development 2000, 127:2347-2355.
47. Pazour GJ, Dickert BL, Vucica Y, et al.: Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene tg737, are required for assembly of cilia and flagella. J Cell Biol 2000, 151:709-718.
48. Haycraft CJ, Swoboda P, Taulman PD, et al.: The C. elegans homolog of the murine cystic kidney disease gene Tg737 functions in a ciliogenic pathway and is disrupted in osm-5 mutant worms. Development 2001, 128:1493-1505.
49. Yoder BK, Tousson A, Millican L, et al.: Polaris, a protein disrupted in orpk mutant mice, is required for assembly of renal cilium. Am J Physiol Renal Physiol 2002, 282:F541-F552.
50. Taulman PD, Haycraft CJ, Balkovetz DF, et al.: Polaris, a protein involved in left-right axis patterning, localizes to basal bodies and cilia. Mol Biol Cell 2001, 12:589-599.
51. Rosenbaum J: Intraflagellar transport. Curr Biol 2002, 12:R125. This excellent review clearly describes the process of intraflagellar transport (IFT). The diseases associated with abnormalities of IFT are discussed.
52. Qin H, Rosenbaum JL, Barr MM: An autosomal recessive polycystic kidney disease gene homolog is involved in intraflagellar transport in C. elegans ciliated sensory neurons. Curr Biol 2001, 11:457-461.
53. Hirokawa N: Kinesin and dynein superfamily proteins and the mechanism of organelle transport. Science 1998, 279:519-526.
54. Marszalek JR, Ruiz-Lozano P, Roberts E, et al.: Situs inversus and embryonic ciliary morphogenesis defects in mouse mutants lacking the KIF3A subunit of kinesin-II. Proc Natl Acad Sci USA 1999, 96:5043-5048.
55. Nonaka S, Tanaka Y, Okada Y, et al.: Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell 1998, 95:829-837.
56. Lin F, Hiesberger T, Cordes K, et al.: Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease. Proc Natl Acad Sci USA 2003, 100:5286-5291. The authors describe a kidney-specific mouse knockout of kif3a in which the mutant mice develop cysts in the kidney and have no cilia in cystic epithelial cells. This study provides direct evidence for a role of cilia in renal cystogenesis.
57. Moon RT, Bowerman B, Boutros M, et al.: The promise and perils of Wnt signaling through beta-catenin. Science 2002, 296:1644-1646.
58. Ward CJ, Yuan D, Masyuk TV, et al.: Cellular and subcellular localization of the ARPKD protein; fibrocystin is expressed on primary cilia. Hum Mol Genet 2003, 12:2703-2710. This is a recent study using newly generated antibodies to the PKDH1 gene product, fibrocystin, to localize the expression of fibrocystin in developing and adult mouse tissues, kidneys of normal human and ARPKD patients, and Madin-Darby canine kidney epithelial cells. Fibrocystin is localized to the cilia.
59. Yoder BK, Hou X, Guay-Woodford LM: The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia. J Am Soc Nephrol 2002, 13:2508-2516. This excellent review clearly describes the process of intraflagellar transport (IFT). The diseases associated with abnormalities of IFT are discussed.
60. Otto EA, Schermer B, Obara T, et al.: Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination. Nat Genet 2003, 34:413-420. Nephronophthisis is a disease entity associated with renal cyst formation/fibrosis and extrarenal presentations. The authors report that mutation of inversin is the genetic cause of nephronophthisis type 2. Inversin is expressed in the primary cilia in association with β-tubulin and nephrocystin, the protein mutated in nephronophthisis type 1. This report strengthens the theory that cilia may be a common pathway in various cystic diseases of the kidney. The authors link ciliary inversin with microtubules, suggesting that cilia and inversin may influence mitotic spindle formation and cell division, and thereby impact cell proliferation.
61. Praetorius HA, Spring KR: Bending the MDCK cell primary cilium increases intracellular calcium. J Membr Biol 2001, 184:71-79.
62. Schwartz EA, Leonard ML, Bizios R, et al.: Analysis and modeling of the primary cilium bending response to fluid shear. Am J Physiol 1997, 272: F132-F138.
63. 2+]i signaling in native mammalian collecting duct ciliated principal cells and nonciliated intercalated cells.
64. 2+]i is cilia dependent. Polycystin-1 and -2 share a common mechanotransduction pathway in kidney epithelial cells.
65. 21, an inhibitor of cell cycle progression, and causes cell cycle arrest. The authors show that the JAK-STAT signaling pathway is the downstream effector. This pathway is defective in pkd1 mutant mice, which leads to dysregulated cell growth in PKD.
66. Nurnberger J, Bacallao RL, Phillips CL: Inversin forms a complex with catenins and N-cadherin in polarized epithelial cells. Mol Biol Cell 2002, 13:3096-3106.
67. Morgan D, Eley L, Sayer J, et al.: Expression analyses and interaction with the anaphase promoting complex protein Apc2 suggest a role for inversin in primary cilia and involvement in the cell cycle. Hum Mol Genet 2002, 11:3345-3350.
68. Ansley SJ, Badano JL, Blacque OE, et al.: Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome. Nature 2003, 425:628-633.