Ciliopathies: an expanding disease spectrum

Abstract

Ciliopathies comprise a group of disorders associated with genetic mutations encoding defective proteins, which result in either abnormal formation or function of cilia. As cilia are a component of almost all vertebrate cells, cilia dysfunction can manifest as a constellation of features that include characteristically, retinal degeneration, renal disease and cerebral anomalies. Additional manifestations include congenital fibrocystic diseases of the liver, diabetes, obesity and skeletal dysplasias. Ciliopathic features have been associated with mutations in over 40 genes to date. However, with over 1,000 polypeptides currently identified within the ciliary proteome, several other disorders associated with this constellation of clinical features will likely be ascribed to mutations in other ciliary genes. The mechanisms underlying many of the disease phenotypes associated with ciliary dysfunction have yet to be fully elucidated. Several elegant studies have crucially demonstrated the dynamic ciliary localisation of components of the Hedgehog and Wnt signalling pathways during signal transduction. Given the critical role of the cilium in transducing “outside-in” signals, it is not surprising therefore, that the disease phenotypes consequent to ciliary dysfunction are a manifestation of aberrant signal transduction. Further investigation is now needed to explore the developmental and physiological roles of aberrant signal transduction in the manifestation of ciliopathy phenotypes. Utilisation of conditional and inducible murine models to delete or overexpress individual ciliary genes in a spatiotemporal and organ/cell-specific manner should help clarify some of the functional roles of ciliary proteins in the manifestation of phenotypic features.

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References

  1. 1.

    Ansley SJ, Badano JL, Blacque OE, Hill J, Hoskins BE, Leitch CC, Kim JC, Ross AJ, Eichers ER, Teslovich TM, Mah AK, Johnsen RC, Cavender JC, Lewis RA, Leroux MR, Beales PL, Katsanis N (2003) Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome. Nature 425(6958):628–633

    CAS  Google Scholar 

  2. 2.

    Li JB, Gerdes JM, Haycraft CJ, Fan Y, Teslovich TM, May-Simera H, Li H, Blacque OE, Li L, Leitch CC, Lewis RA, Green JS, Parfrey PS, Leroux MR, Davidson WS, Beales PL, Guay-Woodford LM, Yoder BK, Stormo GD, Katsanis N, Dutcher SK (2004) Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene. Cell 117(4):541–552

    CAS  Google Scholar 

  3. 3.

    Gherman A, Davis EE, Katsanis N (2006) The ciliary proteome database: an integrated community resource for the genetic and functional dissection of cilia. Nat Genet 38(9):961–962

    CAS  PubMed  Google Scholar 

  4. 4.

    Beales PL, Bland E, Tobin JL, Bacchelli C, Tuysuz B, Hill J, Rix S, Pearson CG, Kai M, Hartley J, Johnson C, Irving M, Elcioglu N, Winey M, Tada M, Scambler PJ (2007) IFT80, which encodes a conserved intraflagellar transport protein, is mutated in Jeune asphyxiating thoracic dystrophy. Nat Genet 39(6):727–729

    CAS  Google Scholar 

  5. 5.

    Nonaka S, Tanaka Y, Okada Y, Takeda S, Harada A, Kanai Y, Kido M, Hirokawa N (1998) Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell 95(6):829–837

    CAS  Google Scholar 

  6. 6.

    Satir P, Guerra C, Bell AJ (2007) Evolution and persistence of the cilium. Cell Motil Cytoskeleton 64(12):906–913

    PubMed  Google Scholar 

  7. 7.

    Woolley D (2000) The molecular motors of cilia and eukaryotic flagella. Essays Biochem 35:103–115

    CAS  PubMed  Google Scholar 

  8. 8.

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

    CAS  PubMed  Google Scholar 

  9. 9.

    Nachury MV, Loktev AV, Zhang Q, Westlake CJ, Peranen J, Merdes A, Slusarski DC, Scheller RH, Bazan JF, Sheffield VC, Jackson PK (2007) A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell 129(6):1201–1213

    CAS  Google Scholar 

  10. 10.

    Pedersen LB, Rosenbaum JL (2008) Intraflagellar transport (IFT) role in ciliary assembly, resorption and signalling. Curr Top Dev Biol 85:23–61

    CAS  Google Scholar 

  11. 11.

    Cole DG, Snell WJ (2009) SnapShot: intraflagellar transport. Cell 137(4):784–784, e1

    CAS  PubMed  Google Scholar 

  12. 12.

    Lin F, Hiesberger T, Cordes K, Sinclair AM, Goldstein LS, Somlo S, Igarashi P (2003) Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease. Proc Natl Acad Sci USA 100(9):5286–5291

    CAS  Google Scholar 

  13. 13.

    Moyer JH, Lee-Tischler MJ, Kwon HY, Schrick JJ, Avner ED, Sweeney WE, Godfrey VL, Cacheiro NL, Wilkinson JE, Woychik RP (1994) Candidate gene associated with a mutation causing recessive polycystic kidney disease in mice. Science 264(5163):1329–1333

    CAS  Google Scholar 

  14. 14.

    Ogden SK, Fei DL, Schilling NS, Ahmed YF, Hwa J, Robbins DJ (2008) G protein Galphai functions immediately downstream of Smoothened in Hedgehog signalling. Nature 456(7224):967–970

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Milenkovic L, Scott MP, Rohatgi R (2009) Lateral transport of Smoothened from the plasma membrane to the membrane of the cilium. J Cell Biol 187(3):365–374

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Huangfu D, Liu A, Rakeman AS, Murcia NS, Niswander L, Anderson KV (2003) Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426(6962):83–87

    CAS  Google Scholar 

  17. 17.

    Ross AJ, May-Simera H, Eichers ER, Kai M, Hill J, Jagger DJ, Leitch CC, Chapple JP, Munro PM, Fisher S, Tan PL, Phillips HM, Leroux MR, Henderson DJ, Murdoch JN, Copp AJ, Eliot MM, Lupski JR, Kemp DT, Dollfus H, Tada M, Katsanis N, Forge A, Beales PL (2005) Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates. Nat Genet 37(10):1135–1140

    CAS  Google Scholar 

  18. 18.

    Simons M, Gloy J, Ganner A, Bullerkotte A, Bashkurov M, Kronig C, Schermer B, Benzing T, Cabello OA, Jenny A, Mlodzik M, Polok B, Driever W, Obara T, Walz G (2005) Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways. Nat Genet 37(5):537–543

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Gray RS, Abitua PB, Wlodarczyk BJ, Szabo-Rogers HL, Blanchard O, Lee I, Weiss GS, Liu KJ, Marcotte EM, Wallingford JB, Finnell RH (2009) The planar cell polarity effector Fuz is essential for targeted membrane trafficking, ciliogenesis and mouse embryonic development. Nat Cell Biol 11(10):1225–1232

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Bielas SL, Silhavy JL, Brancati F, Kisseleva MV, Al-Gazali L, Sztriha L, Bayoumi RA, Zaki MS, Abdel-Aleem A, Rosti RO, Kayserili H, Swistun D, Scott LC, Bertini E, Boltshauser E, Fazzi E, Travaglini L, Field SJ, Gayral S, Jacoby M, Schurmans S, Dallapiccola B, Majerus PW, Valente EM, Gleeson JG (2009) Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies. Nat Genet 41(9):1032–1036

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Cantagrel V, Silhavy JL, Bielas SL, Swistun D, Marsh SE, Bertrand JY, Audollent S, Attie-Bitach T, Holden KR, Dobyns WB, Traver D, Al-Gazali L, Ali BR, Lindner TH, Caspary T, Otto EA, Hildebrandt F, Glass IA, Logan CV, Johnson CA, Bennett C, Brancati F, Valente EM, Woods CG, Gleeson JG (2008) Mutations in the cilia gene ARL13B lead to the classical form of Joubert syndrome. Am J Hum Genet 83(2):170–179

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Noor A, Windpassinger C, Patel M, Stachowiak B, Mikhailov A, Azam M, Irfan M, Siddiqui ZK, Naeem F, Paterson AD, Lutfullah M, Vincent JB, Ayub M (2008) CC2D2A, encoding a coiled-coil and C2 domain protein, causes autosomal-recessive mental retardation with retinitis pigmentosa. Am J Hum Genet 82(4):1011–1018

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Delous M, Baala L, Salomon R, Laclef C, Vierkotten J, Tory K, Golzio C, Lacoste T, Besse L, Ozilou C, Moutkine I, Hellman NE, Anselme I, Silbermann F, Vesque C, Gerhardt C, Rattenberry E, Wolf MT, Gubler MC, Martinovic J, Encha-Razavi F, Boddaert N, Gonzales M, Macher MA, Nivet H, Champion G, Bertheleme JP, Niaudet P, McDonald F, Hildebrandt F, Johnson CA, Vekemans M, Antignac C, Ruther U, Schneider-Maunoury S, Attie-Bitach T, Saunier S (2007) The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nat Genet 39(7):875–881

    CAS  Google Scholar 

  24. 24.

    Baala L, Romano S, Khaddour R, Saunier S, Smith UM, Audollent S, Ozilou C, Faivre L, Laurent N, Foliguet B, Munnich A, Lyonnet S, Salomon R, Encha-Razavi F, Gubler MC, Boddaert N, de Lonlay P, Johnson CA, Vekemans M, Antignac C, Attie-Bitach T (2007) The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome. Am J Hum Genet 80(1):186–194

    CAS  PubMed  Google Scholar 

  25. 25.

    Parisi MA, Bennett CL, Eckert ML, Dobyns WB, Gleeson JG, Shaw DW, McDonald R, Eddy A, Chance PF, Glass IA (2004) The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome. Am J Hum Genet 75(1):82–91

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Dixon-Salazar T, Silhavy JL, Marsh SE, Louie CM, Scott LC, Gururaj A, Al-Gazali L, Al-Tawari AA, Kayserili H, Sztriha L, Gleeson JG (2004) Mutations in the AHI1 gene, encoding jouberin, cause Joubert syndrome with cortical polymicrogyria. Am J Hum Genet 75(6):979–987

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Sayer JA, Otto EA, O’Toole JF, Nurnberg G, Kennedy MA, Becker C, Hennies HC, Helou J, Attanasio M, Fausett BV, Utsch B, Khanna H, Liu Y, Drummond I, Kawakami I, Kusakabe T, Tsuda M, Ma L, Lee H, Larson RG, Allen SJ, Wilkinson CJ, Nigg EA, Shou C, Lillo C, Williams DS, Hoppe B, Kemper MJ, Neuhaus T, Parisi MA, Glass IA, Petry M, Kispert A, Gloy J, Ganner A, Walz G, Zhu X, Goldman D, Nurnberg P, Swaroop A, Leroux MR, Hildebrandt F (2006) The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nat Genet 38(6):674–681

    CAS  Google Scholar 

  28. 28.

    Coene KL, Roepman R, Doherty D, Afroze B, Kroes HY, Letteboer SJ, Ngu LH, Budny B, van Wijk E, Gorden NT, Azhimi M, Thauvin-Robinet C, Veltman JA, Boink M, Kleefstra T, Cremers FP, van Bokhoven H, de Brouwer AP (2009) OFD1 is mutated in X-linked Joubert syndrome and interacts with LCA5-encoded lebercilin. Am J Hum Genet 85(4):465–481

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Valente EM, Silhavy JL, Brancati F, Barrano G, Krishnaswami SR, Castori M, Lancaster MA, Boltshauser E, Boccone L, Al-Gazali L, Fazzi E, Signorini S, Louie CM, Bellacchio E, Bertini E, Dallapiccola B, Gleeson JG (2006) Mutations in CEP290, which encodes a centrosomal protein, cause pleiotropic forms of Joubert syndrome. Nat Genet 38(6):623–625

    CAS  Google Scholar 

  30. 30.

    Brancati F, Barrano G, Silhavy JL, Marsh SE, Travaglini L, Bielas SL, Amorini M, Zablocka D, Kayserili H, Al-Gazali L, Bertini E, Boltshauser E, D’Hooghe M, Fazzi E, Fenerci EY, Hennekam RC, Kiss A, Lees MM, Marco E, Phadke SR, Rigoli L, Romano S, Salpietro CD, Sherr EH, Signorini S, Stromme P, Stuart B, Sztriha L, Viskochil DH, Yuksel A, Dallapiccola B, Valente EM, Gleeson JG (2007) CEP290 mutations are frequently identified in the oculo-renal form of Joubert syndrome-related disorders. Am J Hum Genet 81(1):104–113

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Coppieters F, Lefever S, Leroy BP, De Baere E (2010) CEP290, a gene with many faces: mutation overview and presentation of CEP290base. Hum Mutat 31(10):1097–1108

    CAS  PubMed  Google Scholar 

  32. 32.

    Murga-Zamalloa CA, Desai NJ, Hildebrandt F, Khanna H (2010) Interaction of ciliary disease protein retinitis pigmentosa GTPase regulator with nephronophthisis-associated proteins in mammalian retinas. Mol Vis 16:1373–1381

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Chang B, Khanna H, Hawes N, Jimeno D, He S, Lillo C, Parapuram SK, Cheng H, Scott A, Hurd RE, Sayer JA, Otto EA, Attanasio M, O’Toole JF, Jin G, Shou C, Hildebrandt F, Williams DS, Heckenlively JR, Swaroop A (2006) In-frame deletion in a novel centrosomal/ciliary protein CEP290/NPHP6 perturbs its interaction with RPGR and results in early-onset retinal degeneration in the rd16 mouse. Hum Mol Genet 15(11):1847–1857

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Murga-Zamalloa CA, Swaroop A, Khanna H (2009) RPGR-containing protein complexes in syndromic and non-syndromic retinal degeneration due to ciliary dysfunction. J Genet 88(4):399–407

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Eley L, Gabrielides C, Adams M, Johnson CA, Hildebrandt F, Sayer JA (2008) Jouberin localizes to collecting ducts and interacts with nephrocystin-1. Kidney Int 74(9):1139–1149

    CAS  PubMed  Google Scholar 

  36. 36.

    Kyttala M, Tallila J, Salonen R, Kopra O, Kohlschmidt N, Paavola-Sakki P, Peltonen L, Kestila M (2006) MKS1, encoding a component of the flagellar apparatus basal body proteome, is mutated in Meckel syndrome. Nat Genet 38(2):155–157

    PubMed  Google Scholar 

  37. 37.

    Smith UM, Consugar M, Tee LJ, McKee BM, Maina EN, Whelan S, Morgan NV, Goranson E, Gissen P, Lilliquist S, Aligianis IA, Ward CJ, Pasha S, Punyashthiti R, Malik Sharif S, Batman PA, Bennett CP, Woods CG, McKeown C, Bucourt M, Miller CA, Cox P, Algazali L, Trembath RC, Torres VE, Attie-Bitach T, Kelly DA, Maher ER, Gattone VH 2nd, Harris PC, Johnson CA (2006) The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat. Nat Genet 38(2):191–196

    CAS  Google Scholar 

  38. 38.

    Tallila J, Jakkula E, Peltonen L, Salonen R, Kestila M (2008) Identification of CC2D2A as a Meckel syndrome gene adds an important piece to the ciliopathy puzzle. Am J Hum Genet 82(6):1361–1367

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Gorden NT, Arts HH, Parisi MA, Coene KL, Letteboer SJ, van Beersum SE, Mans DA, Hikida A, Eckert M, Knutzen D, Alswaid AF, Ozyurek H, Dibooglu S, Otto EA, Liu Y, Davis EE, Hutter CM, Bammler TK, Farin FM, Dorschner M, Topcu M, Zackai EH, Rosenthal P, Owens KN, Katsanis N, Vincent JB, Hildebrandt F, Rubel EW, Raible DW, Knoers NV, Chance PF, Roepman R, Moens CB, Glass IA, Doherty D (2008) CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290. Am J Hum Genet 83(5):559–571

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Mougou-Zerelli S, Thomas S, Szenker E, Audollent S, Elkhartoufi N, Babarit C, Romano S, Salomon R, Amiel J, Esculpavit C, Gonzales M, Escudier E, Leheup B, Loget P, Odent S, Roume J, Gerard M, Delezoide AL, Khung S, Patrier S, Cordier MP, Bouvier R, Martinovic J, Gubler MC, Boddaert N, Munnich A, Encha-Razavi F, Valente EM, Saad A, Saunier S, Vekemans M, Attie-Bitach T (2009) CC2D2A mutations in Meckel and Joubert syndromes indicate a genotype-phenotype correlation. Hum Mutat 30(11):1574–1582

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Caridi G, Murer L, Bellantuono R, Sorino P, Caringella DA, Gusmano R, Ghiggeri GM (1998) Renal-retinal syndromes: association of retinal anomalies and recessive nephronophthisis in patients with homozygous deletion of the NPH1 locus. Am J Kidney Dis 32(6):1059–1062

    CAS  PubMed  Google Scholar 

  42. 42.

    Omran H, Sasmaz G, Haffner K, Volz A, Olbrich H, Melkaoui R, Otto E, Wienker TF, Korinthenberg R, Brandis M, Antignac C, Hildebrandt F (2002) Identification of a gene locus for Senior-Loken syndrome in the region of the nephronophthisis type 3 gene. J Am Soc Nephrol 13(1):75–79

    CAS  PubMed  Google Scholar 

  43. 43.

    Schuermann MJ, Otto E, Becker A, Saar K, Ruschendorf F, Polak BC, Ala-Mello S, Hoefele J, Wiedensohler A, Haller M, Omran H, Nurnberg P, Hildebrandt F (2002) Mapping of gene loci for nephronophthisis type 4 and Senior-Loken syndrome, to chromosome 1p36. Am J Hum Genet 70(5):1240–1246

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Otto E, Hoefele J, Ruf R, Mueller AM, Hiller KS, Wolf MT, Schuermann MJ, Becker A, Birkenhager R, Sudbrak R, Hennies HC, Nurnberg P, Hildebrandt F (2002) A gene mutated in nephronophthisis and retinitis pigmentosa encodes a novel protein, nephroretinin, conserved in evolution. Am J Hum Genet 71(5):1161–1167

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Feather SA, Winyard PJ, Dodd S, Woolf AS (1997) Orofaciodigital syndrome type 1 is another dominant polycystic kidney disease: clinical, radiological and histopathological features of a new kindred. Nephrol Dial Transplant 12(7):1354–1361

    CAS  PubMed  Google Scholar 

  46. 46.

    Ferrante MI, Giorgio G, Feather SA, Bulfone A, Wright V, Ghiani M, Selicorni A, Gammaro L, Scolari F, Woolf AS, Sylvie O, Bernard L, Malcolm S, Winter R, Ballabio A, Franco B (2001) Identification of the gene for orofaciodigital type I syndrome. Am J Hum Genet 68(3):569–576

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Singla V, Romaguera-Ros M, Garcia-Verdugo JM, Reiter JF (2010) Ofd1, a human disease gene, regulates the length and distal structure of centrioles. Dev Cell 18(3):410–424

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Ferrante MI, Zullo A, Barra A, Bimonte S, Messaddeq N, Studer M, Dolle P, Franco B (2006) Orofaciodigital type I protein is required for primary cilia formation and left-right axis specification. Nat Genet 38(1):112–117

    CAS  PubMed  Google Scholar 

  49. 49.

    Perrault I, Delphin N, Hanein S, Gerber S, Dufier JL, Roche O, Defoort-Dhellemmes S, Dollfus H, Fazzi E, Munnich A, Kaplan J, Rozet JM (2007) Spectrum of NPHP6/CEP290 mutations in Leber congenital amaurosis and delineation of the associated phenotype. Hum Mutat 28(4):416

    PubMed  Google Scholar 

  50. 50.

    Marlhens F, Bareil C, Griffoin JM, Zrenner E, Amalric P, Eliaou C, Liu SY, Harris E, Redmond TM, Arnaud B, Claustres M, Hamel CP (1997) Mutations in RPE65 cause Leber’s congenital amaurosis. Nat Genet 17(2):139–141

    CAS  PubMed  Google Scholar 

  51. 51.

    Wang H, den Hollander AI, Moayedi Y, Abulimiti A, Li Y, Collin RW, Hoyng CB, Lopez I, Abboud EB, Al-Rajhi AA, Bray M, Lewis RA, Lupski JR, Mardon G, Koenekoop RK, Chen R (2009) Mutations in SPATA7 cause Leber congenital amaurosis and juvenile retinitis pigmentosa. Am J Hum Genet 84(3):380–387

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Sohocki MM, Sullivan LS, Tirpak DL, Daiger SP (2001) Comparative analysis of aryl-hydrocarbon receptor interacting protein-like 1 (Aipl1), a gene associated with inherited retinal disease in humans. Mamm Genome 12(7):566–568

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Den Hollander AI, Heckenlively JR, van den Born LI, de Kok YJ, van der Velde-Visser SD, Kellner U, Jurklies B, van Schooneveld MJ, Blankenagel A, Rohrschneider K, Wissinger B, Cruysberg JR, Deutman AF, Brunner HG, Apfelstedt-Sylla E, Hoyng CB, Cremers FP (2001) Leber congenital amaurosis and retinitis pigmentosa with Coats-like exudative vasculopathy are associated with mutations in the crumbs homologue 1 (CRB1) gene. Am J Hum Genet 69(1):198–203

    PubMed Central  Google Scholar 

  54. 54.

    Gerber S, Perrault I, Hanein S, Barbet F, Ducroq D, Ghazi I, Martin-Coignard D, Leowski C, Homfray T, Dufier JL, Munnich A, Kaplan J, Rozet JM (2001) Complete exon-intron structure of the RPGR-interacting protein (RPGRIP1) gene allows the identification of mutations underlying Leber congenital amaurosis. Eur J Hum Genet 9(8):561–571

    CAS  PubMed  Google Scholar 

  55. 55.

    Freund CL, Wang QL, Chen S, Muskat BL, Wiles CD, Sheffield VC, Jacobson SG, McInnes RR, Zack DJ, Stone EM (1998) De novo mutations in the CRX homeobox gene associated with Leber congenital amaurosis. Nat Genet 18(4):311–312

    CAS  PubMed  Google Scholar 

  56. 56.

    Den Hollander AI, Johnson K, de Kok YJ, Klebes A, Brunner HG, Knust E, Cremers FP (2001) CRB1 has a cytoplasmic domain that is functionally conserved between human and Drosophila. Hum Mol Genet 10(24):2767–2773

    Google Scholar 

  57. 57.

    Bowne SJ, Sullivan LS, Mortimer SE, Hedstrom L, Zhu J, Spellicy CJ, Gire AI, Hughbanks-Wheaton D, Birch DG, Lewis RA, Heckenlively JR, Daiger SP (2006) Spectrum and frequency of mutations in IMPDH1 associated with autosomal dominant retinitis pigmentosa and leber congenital amaurosis. Invest Ophthalmol Vis Sci 47(1):34–42

    PubMed  PubMed Central  Google Scholar 

  58. 58.

    Friedman JS, Chang B, Kannabiran C, Chakarova C, Singh HP, Jalali S, Hawes NL, Branham K, Othman M, Filippova E, Thompson DA, Webster AR, Andreasson S, Jacobson SG, Bhattacharya SS, Heckenlively JR, Swaroop A (2006) Premature truncation of a novel protein, RD3, exhibiting subnuclear localization is associated with retinal degeneration. Am J Hum Genet 79(6):1059–1070

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Janecke AR, Thompson DA, Utermann G, Becker C, Hubner CA, Schmid E, McHenry CL, Nair AR, Ruschendorf F, Heckenlively J, Wissinger B, Nurnberg P, Gal A (2004) Mutations in RDH12 encoding a photoreceptor cell retinol dehydrogenase cause childhood-onset severe retinal dystrophy. Nat Genet 36(8):850–854

    CAS  PubMed  Google Scholar 

  60. 60.

    O’Dea D, Parfrey PS, Harnett JD, Hefferton D, Cramer BC, Green J (1996) The importance of renal impairment in the natural history of Bardet-Biedl syndrome. Am J Kidney Dis 27(6):776–783

    PubMed  Google Scholar 

  61. 61.

    Barakat AJ, Arianas P, Glick AD, Butler MG (1990) Focal sclerosing glomerulonephritis in a child with Laurence-Moon-Biedl syndrome. Child Nephrol Urol 10(2):109–111

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA (1999) New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. J Med Genet 36(6):437–446

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Tobin JL, Di Franco M, Eichers E, May-Simera H, Garcia M, Yan J, Quinlan R, Justice MJ, Hennekam RC, Briscoe J, Tada M, Mayor R, Burns AJ, Lupski JR, Hammond P, Beales PL (2008) Inhibition of neural crest migration underlies craniofacial dysmorphology and Hirschsprung’s disease in Bardet-Biedl syndrome. Proc Natl Acad Sci USA 105(18):6714–6719

    CAS  PubMed  Google Scholar 

  64. 64.

    Mykytyn K, Nishimura DY, Searby CC, Shastri M, Yen HJ, Beck JS, Braun T, Streb LM, Cornier AS, Cox GF, Fulton AB, Carmi R, Luleci G, Chandrasekharappa SC, Collins FS, Jacobson SG, Heckenlively JR, Weleber RG, Stone EM, Sheffield VC (2002) Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome, a complex human obesity syndrome. Nat Genet 31(4):435–438

    CAS  PubMed  Google Scholar 

  65. 65.

    Nishimura DY, Searby CC, Carmi R, Elbedour K, Van Maldergem L, Fulton AB, Lam BL, Powell BR, Swiderski RE, Bugge KE, Haider NB, Kwitek-Black AE, Ying L, Duhl DM, Gorman SW, Heon E, Iannaccone A, Bonneau D, Biesecker LG, Jacobson SG, Stone EM, Sheffield VC (2001) Positional cloning of a novel gene on chromosome 16q causing Bardet-Biedl syndrome (BBS2). Hum Mol Genet 10(8):865–874

    CAS  PubMed  Google Scholar 

  66. 66.

    Chiang AP, Nishimura D, Searby C, Elbedour K, Carmi R, Ferguson AL, Secrist J, Braun T, Casavant T, Stone EM, Sheffield VC (2004) Comparative genomic analysis identifies an ADP-ribosylation factor-like gene as the cause of Bardet-Biedl syndrome (BBS3). Am J Hum Genet 75(3):475–484

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Mykytyn K, Braun T, Carmi R, Haider NB, Searby CC, Shastri M, Beck G, Wright AF, Iannaccone A, Elbedour K, Riise R, Baldi A, Raas-Rothschild A, Gorman SW, Duhl DM, Jacobson SG, Casavant T, Stone EM, Sheffield VC (2001) Identification of the gene that, when mutated, causes the human obesity syndrome BBS4. Nat Genet 28(2):188–191

    CAS  PubMed  Google Scholar 

  68. 68.

    Katsanis N, Beales PL, Woods MO, Lewis RA, Green JS, Parfrey PS, Ansley SJ, Davidson WS, Lupski JR (2000) Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet-Biedl syndrome. Nat Genet 26(1):67–70

    CAS  PubMed  Google Scholar 

  69. 69.

    Badano JL, Ansley SJ, Leitch CC, Lewis RA, Lupski JR, Katsanis N (2003) Identification of a novel Bardet-Biedl syndrome protein, BBS7, that shares structural features with BBS1 and BBS2. Am J Hum Genet 72(3):650–658

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Nishimura DY, Swiderski RE, Searby CC, Berg EM, Ferguson AL, Hennekam R, Merin S, Weleber RG, Biesecker LG, Stone EM, Sheffield VC (2005) Comparative genomics and gene expression analysis identifies BBS9, a new Bardet-Biedl syndrome gene. Am J Hum Genet 77(6):1021–1033

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Stoetzel C, Laurier V, Davis EE, Muller J, Rix S, Badano JL, Leitch CC, Salem N, Chouery E, Corbani S, Jalk N, Vicaire S, Sarda P, Hamel C, Lacombe D, Holder M, Odent S, Holder S, Brooks AS, Elcioglu NH, Silva ED, Rossillion B, Sigaudy S, de Ravel TJ, Lewis RA, Leheup B, Verloes A, Amati-Bonneau P, Megarbane A, Poch O, Bonneau D, Beales PL, Mandel JL, Katsanis N, Dollfus H (2006) BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus. Nat Genet 38(5):521–524

    CAS  PubMed  Google Scholar 

  72. 72.

    Chiang AP, Beck JS, Yen HJ, Tayeh MK, Scheetz TE, Swiderski RE, Nishimura DY, Braun TA, Kim KY, Huang J, Elbedour K, Carmi R, Slusarski DC, Casavant TL, Stone EM, Sheffield VC (2006) Homozygosity mapping with SNP arrays identifies TRIM32, an E3 ubiquitin ligase, as a Bardet-Biedl syndrome gene (BBS11). Proc Natl Acad Sci USA 103(16):6287–6292

    CAS  PubMed  Google Scholar 

  73. 73.

    Stoetzel C, Muller J, Laurier V, Davis EE, Zaghloul NA, Vicaire S, Jacquelin C, Plewniak F, Leitch CC, Sarda P, Hamel C, de Ravel TJ, Lewis RA, Friederich E, Thibault C, Danse JM, Verloes A, Bonneau D, Katsanis N, Poch O, Mandel JL, Dollfus H (2007) Identification of a novel BBS gene (BBS12) highlights the major role of a vertebrate-specific branch of chaperonin-related proteins in Bardet-Biedl syndrome. Am J Hum Genet 80(1):1–11

    CAS  Google Scholar 

  74. 74.

    Leitch CC, Zaghloul NA, Davis EE, Stoetzel C, Diaz-Font A, Rix S, Alfadhel M, Lewis RA, Eyaid W, Banin E, Dollfus H, Beales PL, Badano JL, Katsanis N (2008) Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome. Nat Genet 40(4):443–448

    CAS  Google Scholar 

  75. 75.

    Kim SK, Shindo A, Park TJ, Oh EC, Ghosh S, Gray RS, Lewis RA, Johnson CA, Attie-Bittach T, Katsanis N, Wallingford JB (2010) Planar cell polarity acts through septins to control collective cell movement and ciliogenesis. Science 329(5997):1337–1340

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Otto EA, Hurd TW, Airik R, Chaki M, Zhou W, Stoetzel C, Patil SB, Levy S, Ghosh AK, Murga-Zamalloa CA, van Reeuwijk J, Letteboer SJ, Sang L, Giles RH, Liu Q, Coene KL, Estrada-Cuzcano A, Collin RW, McLaughlin HM, Held S, Kasanuki JM, Ramaswami G, Conte J, Lopez I, Washburn J, Macdonald J, Hu J, Yamashita Y, Maher ER, Guay-Woodford LM, Neumann HP, Obermuller N, Koenekoop RK, Bergmann C, Bei X, Lewis RA, Katsanis N, Lopes V, Williams DS, Lyons RH, Dang CV, Brito DA, Dias MB, Zhang X, Cavalcoli JD, Nurnberg G, Nurnberg P, Pierce EA, Jackson PK, Antignac C, Saunier S, Roepman R, Dollfus H, Khanna H, Hildebrandt F (2010) Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy. Nat Genet 42(10):840–850

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Badano JL, Leitch CC, Ansley SJ, May-Simera H, Lawson S, Lewis RA, Beales PL, Dietz HC, Fisher S, Katsanis N (2006) Dissection of epistasis in oligogenic Bardet-Biedl syndrome. Nature 439(7074):326–330

    CAS  Google Scholar 

  78. 78.

    Collin GB, Marshall JD, Ikeda A, So WV, Russell-Eggitt I, Maffei P, Beck S, Boerkoel CF, Sicolo N, Martin M, Nishina PM, Naggert JK (2002) Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alstrom syndrome. Nat Genet 31(1):74–78

    CAS  PubMed  Google Scholar 

  79. 79.

    Knorz VJ, Spalluto C, Lessard M, Purvis TL, Adigun FF, Collin GB, Hanley NA, Wilson DI, Hearn T (2010) Centriolar association of ALMS1 and likely centrosomal functions of the ALMS motif-containing proteins C10orf90 and KIAA1731. Mol Biol Cell 21(21):3617–3629

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Pirnar T, Neuhauser EB (1966) Asphyxiating thoracic dystrophy of the newborn. Am J Roentgenol Radium Ther Nucl Med 98(2):358–364

    CAS  PubMed  Google Scholar 

  81. 81.

    Singh M, Ray D, Paul VK, Kumar A (1988) Hydrocephalus in asphyxiating thoracic dystrophy. Am J Med Genet 29(2):391–395

    CAS  PubMed  Google Scholar 

  82. 82.

    Phillips CI, Stokoe NL, Bartholomew RS (1979) Asphyxiating thoracic dystrophy (Jeune’s disease) with retinal aplasia: a sibship of two. J Pediatr Ophthalmol Strabismus 16(5):279–283

    CAS  PubMed  Google Scholar 

  83. 83.

    Hudgins L, Rosengren S, Treem W, Hyams J (1992) Early cirrhosis in survivors with Jeune thoracic dystrophy. J Pediatr 120(5):754–756

    CAS  PubMed  Google Scholar 

  84. 84.

    Haycraft CJ, Zhang Q, Song B, Jackson WS, Detloff PJ, Serra R, Yoder BK (2007) Intraflagellar transport is essential for endochondral bone formation. Development 134(2):307–316

    CAS  PubMed  Google Scholar 

  85. 85.

    Brueton LA, Dillon MJ, Winter RM (1990) Ellis-van creveld syndrome, Jeune syndrome, and renal-hepatic-pancreatic dysplasia: separate entities or disease spectrum? J Med Genet 27(4):252–255

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Ruiz-Perez VL, Ide SE, Strom TM, Lorenz B, Wilson D, Woods K, King L, Francomano C, Freisinger P, Spranger S, Marino B, Dallapiccola B, Wright M, Meitinger T, Polymeropoulos MH, Goodship J (2000) Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis. Nat Genet 24(3):283–286

    CAS  PubMed  Google Scholar 

  87. 87.

    Galdzicka M, Patnala S, Hirshman MG, Cai JF, Nitowsky H, Egeland JA, Ginns EI (2002) A new gene, EVC2, is mutated in Ellis-van Creveld syndrome. Mol Genet Metab 77(4):291–295

    CAS  PubMed  Google Scholar 

  88. 88.

    Ruiz-Perez VL, Blair HJ, Rodriguez-Andres ME, Blanco MJ, Wilson A, Liu YN, Miles C, Peters H, Goodship JA (2007) Evc is a positive mediator of Ihh-regulated bone growth that localises at the base of chondrocyte cilia. Development 134(16):2903–2912

    CAS  PubMed  Google Scholar 

  89. 89.

    Walczak-Sztulpa J, Eggenschwiler J, Osborn D, Brown DA, Emma F, Klingenberg C, Hennekam RC, Torre G, Garshasbi M, Tzschach A, Szczepanska M, Krawczynski M, Zachwieja J, Zwolinska D, Beales PL, Ropers HH, Latos-Bielenska A, Kuss AW (2010) Cranioectodermal dysplasia, Sensenbrenner syndrome, is a ciliopathy caused by mutations in the IFT122 gene. Am J Hum Genet 86(6):949–956

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Gilissen C, Arts HH, Hoischen A, Spruijt L, Mans DA, Arts P, van Lier B, Steehouwer M, van Reeuwijk J, Kant SG, Roepman R, Knoers NV, Veltman JA, Brunner HG (2010) Exome sequencing identifies WDR35 variants involved in Sensenbrenner syndrome. Am J Hum Genet 87(3):418–423

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Harris PC (2009) Homer W. Smith Award: insights into the pathogenesis of polycystic kidney disease from gene discovery. J Am Soc Nephrol 20(6):1188–1198

    CAS  PubMed  Google Scholar 

  92. 92.

    Geng L, Segal Y, Peissel B, Deng N, Pei Y, Carone F, Rennke HG, Glucksmann-Kuis AM, Schneider MC, Ericsson M, Reeders ST, Zhou J (1996) Identification and localization of polycystin, the PKD1 gene product. J Clin Invest 98(12):2674–2682

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Mochizuki T, Wu G, Hayashi T, Xenophontos SL, Veldhuisen B, Saris JJ, Reynolds DM, Cai Y, Gabow PA, Pierides A, Kimberling WJ, Breuning MH, Deltas CC, Peters DJ, Somlo S (1996) PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 272(5266):1339–1342

    CAS  Google Scholar 

  94. 94.

    Yoder BK, Hou X, Guay-Woodford LM (2002) The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia. J Am Soc Nephrol 13(10):2508–2516

    CAS  Google Scholar 

  95. 95.

    Ward CJ, Yuan D, Masyuk TV, Wang X, Punyashthiti R, Whelan S, Bacallao R, Torra R, LaRusso NF, Torres VE, Harris PC (2003) Cellular and subcellular localization of the ARPKD protein; fibrocystin is expressed on primary cilia. Hum Mol Genet 12(20):2703–2710

    CAS  Google Scholar 

  96. 96.

    Lu W, Peissel B, Babakhanlou H, Pavlova A, Geng L, Fan X, Larson C, Brent G, Zhou J (1997) Perinatal lethality with kidney and pancreas defects in mice with a targetted Pkd1 mutation. Nat Genet 17(2):179–181

    CAS  PubMed  Google Scholar 

  97. 97.

    Piontek K, Menezes LF, Garcia-Gonzalez MA, Huso DL, Germino GG (2007) A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1. Nat Med 13(12):1490–1495

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Qian F, Watnick TJ, Onuchic LF, Germino GG (1996) The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I. Cell 87(6):979–987

    CAS  PubMed  Google Scholar 

  99. 99.

    Pei Y, Watnick T, He N, Wang K, Liang Y, Parfrey P, Germino G, St George-Hyslop P (1999) Somatic PKD2 mutations in individual kidney and liver cysts support a "two-hit" model of cystogenesis in type 2 autosomal dominant polycystic kidney disease. J Am Soc Nephrol 10(7):1524–1529

    CAS  PubMed  Google Scholar 

  100. 100.

    Moser M, Matthiesen S, Kirfel J, Schorle H, Bergmann C, Senderek J, Rudnik-Schoneborn S, Zerres K, Buettner R (2005) A mouse model for cystic biliary dysgenesis in autosomal recessive polycystic kidney disease (ARPKD). Hepatology 41(5):1113–1121

    CAS  PubMed  Google Scholar 

  101. 101.

    Wolf MT, Hildebrandt F (2010) Nephronophthisis. Pediatr Nephrol. doi:https://doi.org/10.1007/s00467-010-1585-z

  102. 102.

    Tory K, Lacoste T, Burglen L, Moriniere V, Boddaert N, Macher MA, Llanas B, Nivet H, Bensman A, Niaudet P, Antignac C, Salomon R, Saunier S (2007) High NPHP1 and NPHP6 mutation rate in patients with Joubert syndrome and nephronophthisis: potential epistatic effect of NPHP6 and AHI1 mutations in patients with NPHP1 mutations. J Am Soc Nephrol 18(5):1566–1575

    CAS  PubMed  Google Scholar 

  103. 103.

    Bergmann C, Fliegauf M, Bruchle NO, Frank V, Olbrich H, Kirschner J, Schermer B, Schmedding I, Kispert A, Kranzlin B, Nurnberg G, Becker C, Grimm T, Girschick G, Lynch SA, Kelehan P, Senderek J, Neuhaus TJ, Stallmach T, Zentgraf H, Nurnberg P, Gretz N, Lo C, Lienkamp S, Schafer T, Walz G, Benzing T, Zerres K, Omran H (2008) Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia. Am J Hum Genet 82(4):959–970

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Wolf MT, Saunier S, O’Toole JF, Wanner N, Groshong T, Attanasio M, Salomon R, Stallmach T, Sayer JA, Waldherr R, Griebel M, Oh J, Neuhaus TJ, Josefiak U, Antignac C, Otto EA, Hildebrandt F (2007) Mutational analysis of the RPGRIP1L gene in patients with Joubert syndrome and nephronophthisis. Kidney Int 72(12):1520–1526

    CAS  PubMed  Google Scholar 

  105. 105.

    Yokoyama T, Copeland NG, Jenkins NA, Montgomery CA, Elder FF, Overbeek PA (1993) Reversal of left-right asymmetry: a situs inversus mutation. Science 260(5108):679–682

    CAS  PubMed  Google Scholar 

  106. 106.

    Kim YS, Kang HS, Herbert R, Beak JY, Collins JB, Grissom SF, Jetten AM (2008) Kruppel-like zinc finger protein Glis2 is essential for the maintenance of normal renal functions. Mol Cell Biol 28(7):2358–2367

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Woolf AS, Price KL, Scambler PJ, Winyard PJ (2004) Evolving concepts in human renal dysplasia. J Am Soc Nephrol 15(4):998–1007

    PubMed  Google Scholar 

  108. 108.

    Sheffield VC, Carmi R, Kwitek-Black A, Rokhlina T, Nishimura D, Duyk GM, Elbedour K, Sunden SL, Stone EM (1994) Identification of a Bardet-Biedl syndrome locus on chromosome 3 and evaluation of an efficient approach to homozygosity mapping. Hum Mol Genet 3(8):1331–1335

    CAS  PubMed  Google Scholar 

  109. 109.

    Yoder BK, Richards WG, Sweeney WE, Wilkinson JE, Avener ED, Woychik RP (1995) Insertional mutagenesis and molecular analysis of a new gene associated with polycystic kidney disease. Proc Assoc Am Physicians 107(3):314–323

    CAS  PubMed  Google Scholar 

  110. 110.

    Hou X, Mrug M, Yoder BK, Lefkowitz EJ, Kremmidiotis G, D’Eustachio P, Beier DR, Guay-Woodford LM (2002) Cystin, a novel cilia-associated protein, is disrupted in the cpk mouse model of polycystic kidney disease. J Clin Invest 109(4):533–540

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Saburi S, Hester I, Fischer E, Pontoglio M, Eremina V, Gessler M, Quaggin SE, Harrison R, Mount R, McNeill H (2008) Loss of Fat4 disrupts PCP signaling and oriented cell division and leads to cystic kidney disease. Nat Genet 40(8):1010–1015

    CAS  Google Scholar 

  112. 112.

    Fischer E, Pontoglio M (2006) Planar cell polarity and polycystic kidney disease. Med Sci (Paris) 22(6–7):576–578

    Google Scholar 

  113. 113.

    Nishio S, Tian X, Gallagher AR, Yu Z, Patel V, Igarashi P, Somlo S (2010) Loss of oriented cell division does not initiate cyst formation. J Am Soc Nephrol 21(2):295–302

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Karner CM, Chirumamilla R, Aoki S, Igarashi P, Wallingford JB, Carroll TJ (2009) Wnt9b signaling regulates planar cell polarity and kidney tubule morphogenesis. Nat Genet 41(7):793–799

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Harris PC, Torres VE (2009) Polycystic kidney disease. Annu Rev Med 60:321–337

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Saadi-Kheddouci S, Berrebi D, Romagnolo B, Cluzeaud F, Peuchmaur M, Kahn A, Vandewalle A, Perret C (2001) Early development of polycystic kidney disease in transgenic mice expressing an activated mutant of the beta-catenin gene. Oncogene 20(42):5972–5981

    CAS  Google Scholar 

  117. 117.

    Attanasio M, Uhlenhaut NH, Sousa VH, O’Toole JF, Otto E, Anlag K, Klugmann C, Treier AC, Helou J, Sayer JA, Seelow D, Nurnberg G, Becker C, Chudley AE, Nurnberg P, Hildebrandt F, Treier M (2007) Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis. Nat Genet 39(8):1018–1024

    CAS  Google Scholar 

  118. 118.

    Walz G, Budde K, Mannaa M, Nurnberger J, Wanner C, Sommerer C, Kunzendorf U, Banas B, Horl WH, Obermuller N, Arns W, Pavenstadt H, Gaedeke J, Buchert M, May C, Gschaidmeier H, Kramer S, Eckardt KU (2010) Everolimus in patients with autosomal dominant polycystic kidney disease. N Engl J Med 363(9):830–840

    CAS  PubMed  Google Scholar 

  119. 119.

    Hogan MC, Masyuk TV, Page LJ, Kubly VJ, Bergstralh EJ, Li X, Kim B, King BF, Glockner J, Holmes DR III, Rossetti S, Harris PC, LaRusso NF, Torres VE (2010) Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease. J Am Soc Nephrol 21(6):1052–1061

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Johnson CA, Gissen P, Serfi C (2003) Molecular pathology and genetics of congenital hepatorenal fibrocystic syndromes. J Med Genet 40(5):311–319

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Masyuk AI, Masyuk TV, LaRusso NF (2008) Cholangiocyte primary cilia in liver health and disease. Dev Dyn 237(8):2007–2012

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Masyuk TV, Masyuk AI, Torres VE, Harris PC, LaRusso NF (2007) Octreotide inhibits hepatic cystogenesis in a rodent model of polycystic liver disease by reducing cholangiocyte adenosine 3', 5'-cyclic monophosphate. Gastroenterology 132(3):1104–1116

    CAS  PubMed  Google Scholar 

  123. 123.

    Brancati F, Iannicelli M, Travaglini L, Mazzotta A, Bertini E, Boltshauser E, D’Arrigo S, Emma F, Fazzi E, Gallizzi R, Gentile M, Loncarevic D, Mejaski-Bosnjak V, Pantaleoni C, Rigoli L, Salpietro CD, Signorini S, Stringini GR, Verloes A, Zabloka D, Dallapiccola B, Gleeson JG, Valente EM (2009) MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert Syndrome related disorder with liver involvement. Hum Mutat 30(2):E432–E442

    PubMed  PubMed Central  Google Scholar 

  124. 124.

    Meeker WR Jr, Nighbert EJ (1971) Association of cystic dilatation of intrahepatic and common bile ducts with Laurence-Moon-Biedl-Bardet syndrome. Am J Surg 122:822–824

    PubMed  Google Scholar 

  125. 125.

    Kennedy B, Malicki J (2009) What drives cell morphogenesis: a look inside the vertebrate photoreceptor. Dev Dyn 238:2115–2138

    PubMed  PubMed Central  Google Scholar 

  126. 126.

    Young RW (1967) The renewal of photoreceptor cell outer segments. J Cell Biol 33:61–72

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Fath MA, Mullins RF, Searby C, Nishimura DY, Wei J, Rahmouni K, Davis RE, Tayeh MK, Andrews M, Yang B, Sigmund CD, Stone EM, Sheffield VC (2005) Mkks-null mice have a phenotype resembling Bardet-Biedl syndrome. Hum Mol Genet 14:1109–1118

    CAS  PubMed  Google Scholar 

  128. 128.

    Pazour GJ, Baker SA, Deane JA, Cole DG, Dickert BL, Rosenbaum JL, Witman GB, Besharse JC (2002) The intraflagellar transport protein, IFT88, is essential for vertebrate photoreceptor assembly and maintenance. J Cell Biol 157:103–113

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129.

    Moritz OL, Tam BM, Hurd LL, Peranen J, Deretic D, Papermaster DS (2001) Mutant rab8 impairs docking and fusion of rhodopsin-bearing post-Golgi membranes and causes cell death of transgenic Xenopus rods. Mol Biol Cell 12(8):2341–2351

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

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

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We graciously acknowledge Professor Neil Sebire (Department of Pathology), Dr Ken Nischal (Department of Opthalmology), Dr Detlef Bockenhauer and Dr Stephen Marks (Department of Nephro-Urology) at Great Ormond Street Hospital for their contribution of the clinical images. Aoife Waters is supported by the Medical Research Council, UK, and Philip Beales is supported by the Wellcome Trust, UK.

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Correspondence to Aoife M. Waters.

Additional information

Answers

1. d

2. d

3. a

4. a

Electronic supplementary material

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Supplementary Table 1

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Supplementary Table 2

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Supplementary Table 3

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Multiple choice questions (answers appear following the references)

  1. 1.

    Characteristic clinical features of a “Ciliopathy” DO NOT include:

    1. a)

      Renal disease

    2. b)

      Retinal disease

    3. c)

      Cerebral malformations

    4. d)

      Abdominal distension

  2. 2.

    Ciliopathic syndromes DO NOT include:

    1. a)

      Joubert syndrome

    2. b)

      Bardet–Biedl syndrome

    3. c)

      Orofaciodigital syndrome

    4. d)

      Atypical haemolytic uraemic syndrome

  3. 3.

    What is the most common genetic cause of NPHP:

    1. a)

      NPHP1

    2. b)

      NPHP4

    3. c)

      SDCCAG8

    4. d)

      NPHP5

    5. e)

      XNPEP3

  4. 4.

    A molecular diagnosis can be made in what percentage of cases of NPHP

    1. a)

      25%

    2. b)

      40%

    3. c)

      60%

    4. d)

      10%

    5. e)

      70%

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Waters, A.M., Beales, P.L. Ciliopathies: an expanding disease spectrum. Pediatr Nephrol 26, 1039–1056 (2011). https://doi.org/10.1007/s00467-010-1731-7

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Keywords

  • Ciliopathy
  • Renal disease
  • Retinal disease
  • Heterogeneous