Advertisement

Classical Polycystic Kidney Disease: Gene Structures and Mutations and Protein Structures and Functions

  • Emilie Cornec-Le Gall
  • Peter C. HarrisEmail author
Chapter

Abstract

The polycystic kidney disease genes, PKD1 and PKD2, in the autosomal dominant form of the disease (ADPKD), and PKHD1 in the rarer, severe recessive form (ARPKD), were identified ~20 and ~15 years ago, respectively. Since then, advances in the description of the protein products of the PKD genes, engineering of different murine models, and genotype-phenotype correlation studies in patient cohorts have enhanced our understanding of pathogenesis and the course of these life-threatening disorders. Here, we provide an update on PKD gene structures, mutation spectra, and related phenotypes, as well as on the structure, localization, trafficking, and functions of the PKD proteins, polycystin-1 and polycystin-2 (ADPKD) and fibrocystin/polyductin (ARPKD). We also discuss insights from rodent models in both diseases, and particularly how they have underlined the importance of allelic dosage in ADPKD and helped to decipher the conundrum of phenotype variability. Our hope is that the upcoming identification of modifier genes will further help to unravel new pathways and identify key determinants acting in PKD pathophysiology.

Keywords

PKD1 PKD2 PKHD1 Polycystin-1 Polycystin-2 Fibrocystin 

Notes

Acknowledgments

These studies are supported by funding from the NIDDK (DK058816, DK059597, DK079856, and the Mayo Translational PKD Center: DK090728), the PKD Foundation, the Zell Family Foundation, Robert M. and Billie Kelley Pirnie, and the Mayo Clinic. ECLG is a recipient of an ASN Kidney Research Fellowship.

References

  1. 1.
    Torres VE, Harris PC, Pirson Y. Autosomal dominant polycystic kidney disease. Lancet. 2007;369(9569):1287–301.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Harris P, Torres VE. Polycystic kidney disease, autosomal dominant. GeneReviews [Internet]; Genetic Disease Online Reviews at GeneTests-GeneClinics (University of Washington, Seattle) http://www.genetests.org/ 2015 [updated 2015]; Available from: httw://www.geneclinics.org.
  3. 3.
    Reeders ST, Zerres K, Gal A, Hogenkamp T, Propping P, Schmidt W, et al. Prenatal diagnosis of autosomal dominant polycystic kidney disease with a DNA probe. Lancet. 1986;ii:6–8.CrossRefGoogle Scholar
  4. 4.
    Grantham JJ, Torres VE, Chapman AB, Guay-Woodford LM, Bae KT, King BF Jr, et al. Volume progression in polycystic kidney disease. N Engl J Med. 2006;354:2122–30.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Bae K, Park B, Sun H, Wang J, Tao C, Chapman AB, et al. Segmentation of individual renal cysts from MR images in patients with autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol: CJASN. 2013;8(7):1089–97.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Grantham JJ, Mulamalla S, Swenson-Fields KI. Why kidneys fail in autosomal dominant polycystic kidney disease. Nat Rev Nephrol. 2011;7(10):556–66.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Rossetti S, Strmecki L, Gamble V, Burton S, Sneddon V, Peral B, et al. Mutation analysis of the entire PKD1 gene: genetic and diagnostic implications. Am J Hum Genet. 2001;68(1):46–63.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Reeders ST, Breuning MH, Davies KE, Nicholls RD, Jarman AP, Higgs DR, et al. A highly polymorphic DNA marker linked to adult polycystic kidney disease on chromosome 16. Nature. 1985;317:542–4.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Consortium EPKD. The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. Cell. 1994;77(6):881–94.CrossRefGoogle Scholar
  10. 10.
    Hughes J, Ward CJ, Peral B, Aspinwall R, Clark K, San Millán JL, et al. The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains. Nat Genet. 1995;10(2):151–60.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    International Polycystic Kidney Disease Consortium. Polycystic kidney disease: the complete structure of the PKD1 gene and its protein. Cell. 1995;81(2):289–98.CrossRefGoogle Scholar
  12. 12.
    Loftus BJ, Kim U-J, Sneddon VP, Kalush F, Brandon R, Fuhrmann J, et al. Genome duplications and other features in 12 Mbp of DNA sequence from human chromosome 16p and 16q. Genomics. 1999;60:295–308.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Phakdeekitcharoen B, Watnick T, Germino GG. Mutation analysis of the entire replicated portion of PKD1 using genomic DNA samples. J Am Soc Nephrol. 2001;12:955–63.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Kimberling WJ, Fain PR, Kenyon JB, Goldgar D, Sujansky E, Gabow PA. Linkage heterogeneity of autosomal dominant polycystic kidney disease. N Engl J Med. 1988;319:913–8.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Peters DJM, Spruit L, Saris JJ, Ravine D, Sandkuijl LA, Fossdal R, et al. Chromosome 4 localization of a second gene for autosomal dominant polycystic kidney disease. Nat Genet. 1993;5:359–62.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Mochizuki T, Wu G, Hayashi T, Xenophontos SL, Veldhusien B, Saris JJ, et al. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science. 1996;272(5266):1339–42.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Daoust MC, Reynolds DM, Bichet DG, Somlo S. Evidence for a third genetic locus for autosomal dominant polycystic kidney disease. Genomics. 1995;25:733–6.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    de Almeida S, de Almeida E, Peters D, Pinto JR, Távora I, Lavinha J, et al. Autosomal dominant polycystic kidney disease: evidence for the existence of a third locus in a Portuguese family. Hum Genet. 1995;96:83–8.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Bogdanova N, Dworniczak B, Dragova D. Genetic heterogeneity of polycystic kidney disease in Bulgaria. Hum Genet. 1995;95:645–50.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Turco AE, Clementi M, Rossetti S, Tenconi R, Pignatti PF. An Italian family with autosomal dominant polycystic kidney disease unlinked to either the PKD1 or PKD2 gene. Am J Kidney Dis. 1996;28(5):759–61.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Ariza M, Alvarez V, Marin R, Aguado S, Lopez-Larrea C, Alvarez J, et al. A family with a milder form of adult dominant polycystic kidney disease not linked to the PKD1 (16p) or PKD2 (4q) genes. J Med Genet. 1997;34(7):587–9.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Paul BM, Consugar MB, Ryan Lee M, Sundsbak JL, Heyer CM, Rossetti S, et al. Evidence of a third ADPKD locus is not supported by re-analysis of designated PKD3 families. Kidney Int. 2014;85(2):383–92.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Porath B, Gainullin VG, Cornec-Le Gall E, Dillinger EK, Heyer CM, Hopp K, Edwards ME, Madsen CD, Mauritz SR, Banks CJ, Baheti S, Reddy B, Herrero JI, Banales JM, Hogan MC, Tasic V, Watnick TJ, Chapman AB, Vigneau C, Lavainne F, Audrezet MP, Ferec C, Le Meur Y, Torres VE, Genkyst Study Group HPoPKDG, Consortium for Radiologic Imaging Studies of Polycystic Kidney D, Harris PC. Mutations in GANAB, Encoding the Glucosidase IIalpha Subunit, Cause Autosomal-Dominant Polycystic Kidney and Liver Disease. Am J Hum Genet. 2016;98:1193–207.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Besse W, Dong K, Choi J, Punia S, Fedeles SV, Choi M, Gallagher AR, Huang EB, Gulati A, Knight J, Mane S, Tahvanainen E, Tahvanainen P, Sanna-Cherchi S, Lifton RP, Watnick T, Pei YP, Torres VE, Somlo S. Isolated polycystic liver disease genes define effectors of polycystin-1 function. J Clin Invest. 2017;127:1772–85.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Rossetti S, Chauveau D, Walker D, Saggar-Malik A, Winearls CG, Torres VE, et al. A complete mutation screen of the ADPKD genes by DHPLC. Kidney Int. 2002;61(5):1588–99.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Rossetti S, Consugar MB, Chapman AB, Torres VE, Guay-Woodford LM, Grantham JJ, et al. Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2007;18(7):2143–60.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Audrezet MP, Cornec-Le Gall E, Chen JM, Redon S, Quere I, Creff J, et al. Autosomal dominant polycystic kidney disease: comprehensive mutation analysis of PKD1 and PKD2 in 700 unrelated patients. Hum Mutat. 2012;33(8):1239–50.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Rossetti S, Hopp K, Sikkink RA, Sundsbak JL, Lee YK, Kubly V, et al. Identification of gene mutations in autosomal dominant polycystic kidney disease through targeted resequencing. J Am Soc Nephrol. 2012;23(5):915–33.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Tan AY, Michaeel A, Liu G, Elemento O, Blumenfeld J, Donahue S, et al. Molecular diagnosis of autosomal dominant polycystic kidney disease using next-generation sequencing. J Mol Diagn. 2014;16(2):216–28.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Trujillano D, Bullich G, Ossowski S, Ballarin J, Torra R, Estivill X, et al. Diagnosis of autosomal dominant polycystic kidney disease using efficient PKD1 and PKD2 targeted next-generation sequencing. Mol Genet Genomic Med. 2014;2(5):412–21.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Yang T, Meng Y, Wei X, Shen J, Zhang M, Qi C, et al. Identification of novel mutations of PKD1 gene in Chinese patients with autosomal dominant polycystic kidney disease by targeted next-generation sequencing. Clin Chim Acta. 2014;433:12–9.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Consugar MB, Wong WC, Lundquist PA, Rossetti S, Kubly V, Walker DL, et al. Characterization of large rearrangements in autosomal dominant polycystic kidney disease and the PKD1/TSC2 contiguous gene syndrome. Kidney Int. 2008;74(11):1468–79.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Cornec-Le Gall E, Audrezet MP, Chen JM, Hourmant M, Morin MP, Perrichot R, et al. Type of PKD1 mutation influences renal outcome in ADPKD. J Am Soc Nephrol. 2013;24(6):1006–13.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Hwang YH, Conklin J, Chan W, Roslin NM, Liu J, He N, et al. Refining genotype-phenotype correlation in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2016;27(6):1861–8.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Drenth JP, Te Morsche RH, Smink R, Bonifacino JS, Jansen JB. Germline mutations in PRKCSH are associated with autosomal dominant polycystic liver disease. Nat Genet. 2003;33:345–7.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Li A, Davila S, Furu L, Qian Q, Tian X, Kamath PS, et al. Mutations in PRKCSH cause isolated autosomal dominant polycystic liver disease. Am J Hum Genet. 2003;72:691–703.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Davila S, Furu L, Gharavi AG, Tian X, Onoe T, Qian Q, et al. Mutations in SEC63 cause autosomal dominant polycystic liver disease. Nat Genet. 2004;36(6):575–7.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Heidet L, Decramer S, Pawtowski A, Moriniere V, Bandin F, Knebelmann B, et al. Spectrum of HNF1B mutations in a large cohort of patients who harbor renal diseases. Clin J Am Soc Nephrol. 2010;5(6):1079–90.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Cnossen WR, Te Morsche RH, Hoischen A, Gilissen C, Chrispijn M, Venselaar H, et al. Whole-exome sequencing reveals LRP5 mutations and canonical Wnt signaling associated with hepatic cystogenesis. Proc Natl Acad Sci U S A. 2014;111(14):5343–8.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Cnossen WR, Te Morsche RH, Hoischen A, Gilissen C, Venselaar H, Mehdi S, et al. LRP5 variants may contribute to ADPKD. Eur J Hum Genet. 2016;24:237–42.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Rossetti S, Kubly V, Consugar MB, van’t Hoff WG, Niaduet WP, Torres VE, et al. Incompletely penetrant PKD1 alleles associated with mild, homozygous or in utero onset PKD. J Am Soc Nephrol. 2009;18:848–55.Google Scholar
  42. 42.
    Vujic M, Heyer CM, Ars E, Hopp K, Markoff A, Orndal C, et al. Incompletely penetrant PKD1 alleles mimic the renal manifestations of ARPKD. J Am Soc Nephrol. 2010;21(7):1097–102.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Autosomal dominant polycystic kidney disease mutation database [database on the Internet] 2015 [accessed October 2015]. Available from: http://pkdb.mayo.edu.
  44. 44.
    Pei Y, Paterson AD, Wang KR, He N, Hefferton D, Watnick T, et al. Bilineal disease and trans-heterozygotes in autosomal dominant polycystic kidney disease. Am J Hum Genet. 2001;68:355–63.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Watnick TJ, Gandolph MA, Weber H, Neumann HPH, Germino GG. Gene conversion is a likely cause of mutation in PKD1. Hum Mol Genet. 1998;7:1239–43.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Tan AY, Blumenfeld J, Michaeel A, Donahue S, Bobb W, Parker T, et al. Autosomal dominant polycystic kidney disease caused by somatic and germline mosaicism. Clin Genet. 2015;87(4):373–7.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Reiterova J, Stekrova J, Merta M, Kotlas J, Elisakova V, Lnenicka P, et al. Autosomal dominant polycystic kidney disease in a family with mosaicism and hypomorphic allele. BMC Nephrol. 2013;14:59.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Connor A, Lunt PW, Dolling C, Patel Y, Meredith AL, Gardner A, et al. Mosaicism in autosomal dominant polycystic kidney disease revealed by genetic testing to enable living related renal transplantation. Am J Transplant. 2008;8(1):232–7.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Hateboer N, van Dijk MA, Bogdanova N, Coto E, Saggar-Malik AK, San Millan JL, et al. Comparison of phenotypes of polycystic kidney disease types 1 and 2. Lancet. 1999;353:103–7.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Rossetti S, Chauveau D, Kubly V, Slezak J, Saggar-Malik A, Pei Y, et al. Association of mutation position in polycystic kidney disease 1 (PKD1) gene and development of a vascular phenotype. Lancet. 2003;361:2196–201.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Bozza A, Aguiari G, Scapoli C, Scalia P, Perini L, De Paoli VE, et al. Autosomal dominant polycystic kidney disease linked to PKD2 locus in a family with severe extrarenal manifestations. Am J Nephrol. 1997;17(5):458–61.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Chebib FT, Jung Y, Heyer CM, Irazabal MV, Hogan MC, Harris PC, Torres VE, El-Zoghby ZM. Effect of genotype on the severity and volume progression of polycystic liver disease in ADPKD. Nephrol Dial Transplant. 2016;31:952–60.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Rossetti S, Burton S, Strmecki L, Pond GR, San Millán JL, Zerres K, 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(5):1230–7.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Magistroni R, He N, Wang K, Andrew R, Johnson A, Gabow P, et al. Genotype-renal function correlation in type 2 autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2003;14(5):1164–74.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Harris PC, Hopp K. The mutation, a key determinant of phenotype in ADPKD. J Am Soc Nephrol. 2013;24(6):868–70.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Cornec-Le Gall E, Audrezet MP, Rousseau A, Hourmant M, Renaudineau E, Charasse C, et al. The PROPKD score: a new algorithm to predict renal survival in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2016;27(3):942–51.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Paterson AD, Wang KR, Lupea D, St George-Hyslop P, Pei Y. Recurrent fetal loss associated with bilineal inheritance of type 1 autosomal dominant polycystic kidney disease. Am J Kidney Dis. 2002;40(1):16–20.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Zerres K, Rudnik-Schöneborn S, Deget F. German working group on paediatric nephrology. Childhood onset autosomal dominant polycystic kidney disease in sibs: clinical picture and recurrence risk. J Med Genet. 1993;30(7):583–8.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Hopp K, Ward CJ, Hommerding CJ, Nasr SH, Tuan HF, Gainullin VG, et al. Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity. J Clin Invest. 2012;122(11):4257–73.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Audrezet MP, Corbiere C, Lebbah S, Moriniere V, Broux F, Louillet F, et al. Comprehensive PKD1 and PKD2 mutation analysis in prenatal autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2016;27(3):722–9.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Losekoot M, Ruivenkamp CA, Tholens AP, Grimbergen JE, Vijfhuizen L, Vermeer S, et al. Neonatal onset autosomal dominant polycystic kidney disease (ADPKD) in a patient homozygous for a PKD2 missense mutation due to uniparental disomy. J Med Genet. 2012;49(1):37–40.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Bergmann C, von Bothmer J, Ortiz Bruchle N, Venghaus A, Frank V, Fehrenbach H, et al. Mutations in multiple PKD genes may explain early and severe polycystic kidney disease. J Am Soc Nephrol. 2011;22(11):2047–56.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Pei Y, Lan Z, Wang K, Garcia-Gonzalez M, He N, Dicks E, et al. A missense mutation in PKD1 attenuates the severity of renal disease. Kidney Int. 2012;81(4):412–7.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Gainullin VG, Hopp K, Ward CJ, Hommerding CJ, Harris PC. Polycystin-1 maturation requires polycystin-2 in a dose-dependent manner. J Clin Invest. 2015;125(2):607–20.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Harris PC, Ward CJ, Peral B, Hughes J. Autosomal dominant polycystic kidney disease: molecular analysis. Hum Mol Genet. 1995;4:1745–9.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Brook-Carter PT, Peral B, Ward CJ, Thompson P, Hughes J, Maheshwar MM, et al. Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease – a contiguous gene syndrome. Nat Genet. 1994;8:328–32.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Sampson JR, Maheshwar MM, Aspinwall R, Thompson P, Cheadle JP, Ravine D, et al. Renal cystic disease in tuberous sclerosis: role of the polycystic kidney disease 1 gene. Am J Hum Genet. 1997;61:843–51.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Kleymenova E, Ibraghimov-Beskrovnaya O, Kugoh H, Everitt J, Xu H, Kiguchi K, et al. Tuberin-dependent membrane localization of polycystin-1: a functional link between polycystic kidney disease and the TSC2 tumor suppressor gene. Mol Cell. 2001;7:823–32.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Shillingford JM, Murcia NS, Larson CH, Low SH, Hedgepeth R, Brown N, et al. The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc Natl Acad Sci U S A. 2006;103(14):5466–71.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Harris PC, Rossetti S. Molecular diagnostics for autosomal dominant polycystic kidney disease. Nat Rev Nephrol. 2010;6(4):197–206.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    MacDermot KD, Saggar-Malik AK, Economides DL, Jeffery S. Prenatal diagnosis of autosomal dominant polycystic kidney disease (PKD1) presenting in utero and prognosis for very early onset disease. J Med Genet. 1998;35:13–6.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Zeevi DA, Renbaum P, Ron-El R, Eldar-Geva T, Raziel A, Brooks B, et al. Preimplantation genetic diagnosis in genomic regions with duplications and pseudogenes: long-range PCR in the single-cell assay. Hum Mutat. 2013;34(5):792–9.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    De Rycke M, Georgiou I, Sermon K, Lissens W, Henderix P, Joris H, et al. PGD for autosomal dominant polycystic kidney disease type 1. Mol Hum Reprod. 2005;11(1):65–71.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Lu W, Peissel B, Babakhanlou H, Pavlova A, Geng L, Fan X, et al. Perinatal lethality with kidney and pancreas defects in mice with a targeted PKD1 mutation. Nat Genet. 1997;17(2):179–81.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Wu G, Somlo S. Molecular genetics and mechanism of autosomal dominant polycystic kidney disease. Mol Genet Metab. 2000;69:1–15.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Lu W, Fan X, Basora N, Babakhanlou H, Law T, Rifai N, et al. Late onset of renal and hepatic cysts in Pkd1-targeted heterozygotes. Nat Genet. 1999;21:160–1.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Wu G, D'Agati V, Cai Y, Markowitz G, Park JH, Reynolds DM, et al. Somatic inactivation of PKD2 results in polycystic kidney disease. Cell. 1998;93(2):177–88.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Torres VE, Wang X, Qian Q, Somlo S, Harris PC, Gattone VH. Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. Nat Med. 2004;10:363–4.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Piontek K, Menezes LF, Garcia-Gonzalez MA, Huso DL, Germino GG. A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1. Nat Med. 2007;13(12):1490–5.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Lantinga-van Leeuwen IS, Leonhard WN, van der Wal A, Breuning MH, de Heer E, Peters DJ. Kidney-specific inactivation of the PKD1 gene induces rapid cyst formation in developing kidneys and a slow onset of disease in adult mice. Hum Mol Genet. 2007;16(24):3188–96.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Shillingford JM, Piontek KB, Germino GG, Weimbs T. Rapamycin ameliorates PKD resulting from conditional inactivation of Pkd1. J Am Soc Nephrol. 2010;21(3):489–97.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Leonhard WN, Zandbergen M, Veraar K, van den Berg S, van der Weerd L, Breuning M, et al. Scattered deletion of PKD1 in kidneys causes a cystic snowball effect and recapitulates polycystic kidney disease. J Am Soc Nephrol: JASN. 2015;26(6):1322–33.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Fedeles SV, Tian X, Gallagher AR, Mitobe M, Nishio S, Lee SH, et al. A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation. Nat Genet. 2011;43(7):639–47.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Lantinga-van Leeuwen IS, Dauwerse JG, Baelde HJ, Leonhard WN, van de Wal A, Ward CJ, et al. Lowering of PKD1 expression is sufficient to cause polycystic kidney disease. Hum Mol Genet. 2004;13(24):3069–77.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Jiang ST, Chiou YY, Wang E, Lin HK, Lin YT, Chi YC, et al. Defining a link with autosomal-dominant polycystic kidney disease in mice with congenitally low expression of Pkd1. Am J Pathol. 2006;168(1):205–20.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Happe H, van der Wal AM, Salvatori DC, Leonhard WN, Breuning MH, de Heer E, et al. Cyst expansion and regression in a mouse model of polycystic kidney disease. Kidney Int. 2013;83(6):1099–108.  https://doi.org/10.1038/ki2013132013.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Hopp K, Hommerding CJ, Wang X, Ye H, Harris PC, Torres VE. Tolvaptan plus Pasireotide shows enhanced efficacy in a PKD1 model. J Am Soc Nephrol. 2014;26(1):39–47.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Reeders ST. Multilocus polycystic disease. Nat Genet. 1992;1:235–7.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Qian F, Watnick TJ, Onuchic LF, Germino GG. The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I. Cell. 1996;87(6):979–87.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Brasier JL, Henske EP. Loss of the polycystic kidney disease (PKD1) region of chromosome 16p13 in renal cyst cells supports a loss-of-function model for cyst pathogenesis. J Clin Invest. 1997;99:194–9.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Watnick TJ, Torres VE, Gandolph MA, Qian F, Onuchic LF, Klinger KW, et al. Somatic mutation in individual liver cysts supports a two-hit model of cystogenesis in autosomal dominant polycystic kidney disease. Mol Cell. 1998;2:247–51.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Harris PC, Bae K, Rossetti S, Torres VE, Grantham JJ, Chapman A, et al. Cyst number but not the rate of cystic growth is associated with the mutated gene in ADPKD. J Am Soc Nephrol. 2006;17(11):3013–9.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Nishio S, Hatano M, Nagata M, Horie S, Koike T, Tokuhisa T, et al. PKD1 regulates immortalized proliferation of renal tubular epithelial cells through p53 induction and JNK activation. J Clin Invest. 2005;115(4):910–8.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Watnick T, He N, Wang K, Liang Y, Parfrey P, Hefferton D, et al. Mutations of PKD1 in ADPKD2 cysts suggest a pathogenic effect of trans-heterozygous mutations. Nat Genet. 2000;25:143–4.PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Koptides M, Mean R, Demetriou K, Pierides A, Deltas CC. Genetic evidence for a trans-heterozygous model for cystogenesis in autosomal dominant polycystic kidney disease. Hum Mol Genet. 2000;9(3):447–52.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Gallagher AR, Germino GG, Somlo S. Molecular advances in autosomal dominant polycystic kidney disease. Adv Chronic Kidney Dis. 2010;17(2):118–30.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Cornec-Le Gall E, Audrezet M, Le Meur Y, Chen J, Ferec C. Genetics and pathogenesis of autosomal dominant polycystic kidney disease: 20 years on. Hum Mutat. 2014. 2014;35(12):1393–406.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Takakura A, Contrino L, Zhou X, Bonventre JV, Sun Y, Humphreys BD, et al. Renal injury is a third hit promoting rapid development of adult polycystic kidney disease. Hum Mol Genet. 2009;18(14):2523–31.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Happé H, Leonhard WN, van der Wal A, van de Water B, Lantinga-van Leeuwen IS, Breuning MH, et al. Toxic tubular injury in kidneys from Pkd1-deletion mice accelerates cystogenesis accompanied by dysregulated planar cell polarity and canonical Wnt signaling pathways. Hum Mol Genet. 2009;18(14):2532–42.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Liu X-G, Shi S, Senthilnathan S, Yu J, Wu E, Bergmann C, et al. Genetic variation of DKK3 may modify renal disease severity in PKD1. J Am Soc Nephrol. 2010;21:1510–20.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Qian F, Germino FJ, Cai Y, Zhang X, Somlo S, Germino GG. PKD1 interacts with PKD2 through a probable coiled-coil domain. Nat Genet. 1997;16(2):179–83.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Oatley P, Stewart AP, Sandford R, Edwardson JM. Atomic force microscopy imaging reveals the domain structure of polycystin-1. Biochemistry. 2012;51(13):2879–88.PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Ong AC, Harris PC. A polycystin-centric view of cyst formation and disease: the polycystins revisited. Kidney Int. 2015;88(4):699–710.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Forman JR, Qamar S, Paci E, Sandford RN, Clarke J. The remarkable mechanical strength of polycystin-1 supports a direct role in mechanotransduction. J Mol Biol. 2005;349(4):861–71.PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Qian F, Wei W, Germino G, Oberhauser A. The nanomechanics of polycystin-1 extracellular region. J Biol Chem. 2005;280(49):40723–30.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Xu M, Ma L, Bujalowski PJ, Qian F, Sutton RB, Oberhauser AF. Analysis of the REJ module of polycystin-1 using molecular modeling and force-spectroscopy techniques. J Biophys. 2013;2013:525231.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Xu Y, Streets AJ, Hounslow AM, Tran U, Jean-Alphonse F, Needham AJ, et al. The polycystin-1, lipoxygenase, and alpha-toxin domain regulates polycystin-1 trafficking. J Am Soc Nephrol. 2016;27:1159–73.PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Qian F, Boletta A, Bhunia AK, Xu H, Liu L, Ahrabi AK, et al. Cleavage of polycystin-1 requires the receptor for egg jelly domain and is disrupted by human autosomal-dominant polycystic kidney disease 1- associated mutations. Proc Natl Acad Sci U S A. 2002;99(26):16981–6.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Yu S, Hackmann K, Gao J, He X, Piontek K, Garcia-Gonzalez MA, et al. Essential role of cleavage of polycystin-1 at G protein-coupled receptor proteolytic site for kidney tubular structure. Proc Natl Acad Sci U S A. 2007;104(47):18688–93.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Kurbegovic A, Kim H, Xu H, Yu S, Cruanes J, Maser RL, et al. Novel functional complexity of polycystin-1 by GPS cleavage in vivo: role in polycystic kidney disease. Mol Cell Biol. 2014;34(17):3341–53.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Chapin HC, Rajendran V, Caplan MJ. Polycystin-1 surface localization is stimulated by polycystin-2 and cleavage at the G protein-coupled receptor proteolytic site. Mol Biol Cell. 2010;21(24):4338–48.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Arac D, Boucard AA, Bolliger MF, Nguyen J, Soltis SM, Sudhof TC, et al. A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis. EMBO J. 2012;31(6):1364–78.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Chauvet V, Tian X, Husson H, Grimm DH, Wang T, Hieseberger T, et al. Mechanical stimuli induce cleavage and nuclear translocation of the polycystin-1 C terminus. J Clin Invest. 2004;114(10):1433–43.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Low SH, Vasanth S, Larson CH, Mukherjee S, Sharma N, Kinter MT, et al. Polycystin-1, STAT6, and P100 function in a pathway that transduces ciliary mechanosensation and is activated in polycystic kidney disease. Dev Cell. 2006;10(1):57–69.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Allen MD, Qamar S, Vadivelu MK, Sandford RN, Bycroft M. A high-resolution structure of the EF-hand domain of human polycystin-2. Protein Sci. 2014;23(9):1301–8.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Celic A, Petri ET, Demeler B, Ehrlich BE, Boggon TJ. Domain mapping of the polycystin-2 C-terminal tail using de novo molecular modeling and biophysical analysis. J Biol Chem. 2008;283(42):28305–12.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Giamarchi A, Feng S, Rodat-Despoix L, Xu Y, Bubenshchikova E, Newby LJ, et al. A polycystin-2 (TRPP2) dimerization domain essential for the function of heteromeric polycystin complexes. EMBO J. 2010;29(7):1176–91.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Yu Y, Ulbrich MH, Li MH, Buraei Z, Chen XZ, Ong AC, et al. Structural and molecular basis of the assembly of the TRPP2/PKD1 complex. Proc Natl Acad Sci U S A. 2009;106(28):11558–63.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Streets AJ, Wessely O, Peters DJ, Ong AC. Hyperphosphorylation of polycystin-2 at a critical residue in disease reveals an essential role for polycystin-1-regulated dephosphorylation. Hum Mol Genet. 2013;22(10):1924–39.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Gonzalez-Perrett S, Kim K, Ibarra C, Damiano AE, Zotta E, Batelli M, et al. Polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease (ADPKD), is a Ca2+-permeable non-selective cation channel. Proc Natl Acad Sci U S A. 2001;98(3):1182–7.PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Koulen P, Cai Y, Geng L, Maeda Y, Nishimura S, Witzgall R, et al. Polycystin-2 is an intracellular calcium release channel. Nat Cell Biol. 2002;4:191–7.PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Shen PS, Yang X, DeCaen PG, Liu X, Bulkley D, Clapham DE, Cao E. The Structure of the Polycystic Kidney Disease Channel PKD2 in Lipid Nanodiscs. Cell, 167. 2016;e711:763–73.CrossRefGoogle Scholar
  123. 123.
    Grieben M, Pike AC, Shintre CA, Venturi E, El-Ajouz S, Tessitore A, Shrestha L, Mukhopadhyay S, Mahajan P, Chalk R, Burgess-Brown NA, Sitsapesan R, Huiskonen JT, Carpenter EP. Structure of the polycystic kidney disease TRP channel Polycystin-2 (PC2). Nat Struct Mol Biol. 2017;24:114–22.PubMedCrossRefPubMedCentralGoogle Scholar
  124. 124.
    Wilkes M, Madej MG, Kreuter L, Rhinow D, Heinz V, De Sanctis S, Ruppel S, Richter RM, Joos F, Grieben M, Pike AC, Huiskonen JT, Carpenter EP, Kuhlbrandt W, Witzgall R, Ziegler C. Molecular insights into lipid-assisted Ca2+ regulation of the TRP channel Polycystin-2. Nat Struct Mol Biol. 2017;24:123–30.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    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(6):881–94.CrossRefGoogle Scholar
  126. 126.
    Markowitz GS, Cai YQ, Li L, Wu GQ, Ward LC, Somlo S, et al. Polycystin-2 expression is developmentally regulated. Am J Physiol – Renal Fluid Electro Physiol. 1999;46(1):F17–25.CrossRefGoogle Scholar
  127. 127.
    Ward CJ, Turley H, Ong ACM, Comley M, Biddolph S, Chetty R, et al. Polycystin, the polycystic kidney disease 1 protein, is expressed by epithelial cells in fetal, adult and polycystic kidney. Proc Natl Acad Sci U S A. 1996;93:1524–8.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Hildebrandt F, Benzing T, Katsanis N. Ciliopathies. New Eng J Med. 2011;364(16):1533–43.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Kim H, Xu H, Yao Q, Li W, Huang Q, Outeda P, et al. Ciliary membrane proteins traffic through the Golgi via a Rabep1/GGA1/Arl3-dependent mechanism. Nat Commun. 2014;5:5482.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Scheffers MS, van der Bent P, Prins F, Spruit L, Breuning MH, Litvinov SV, et al. Polycystin-1, the product of the polycystic kidney disease 1 gene, co-localizes with desmosomes in MDCK cells. Hum Mol Genet. 2000;9(18):2743–50.PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Hogan MC, Manganelli L, Woollard JR, Masyuk AI, Masyuk TV, Tammachote R, et al. Characterization of PKD protein-positive exosome-like vesicles. J Am Soc Nephrol. 2009;20(2):278–88.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Cai Y, Maeda Y, Cedzich A, Torres VE, Wu G, Hayashi T, et al. Identification and characterization of polycystin-2, the PKD2 gene product. J Biol Chem. 1999;274:28557–65.PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Anyatonwu GI, Estrada M, Tian X, Somlo S, Ehrlich BE. Regulation of ryanodine receptor-dependent calcium signaling by polycystin-2. Proc Natl Acad Sci U S A. 2007;104(15):6454–9.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Li Y, Wright JM, Qian F, Germino GG, Guggino WB. Polycystin 2 interacts with type I inositol 1,4,5-trisphosphate receptor to modulate intracellular Ca2+ signaling. J Biol Chem. 2005;280(50):41298–306.PubMedCrossRefPubMedCentralGoogle Scholar
  135. 135.
    Praetorius HA, Spring KR. Bending the MDCK cell primary cilium increases intracellular calcium. J Membr Biol. 2001;184(1):71–9.PubMedCrossRefPubMedCentralGoogle Scholar
  136. 136.
    Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, et al. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet. 2003;33(2):129–37.PubMedCrossRefPubMedCentralGoogle Scholar
  137. 137.
    Delling M, DeCaen PG, Doerner JF, Febvay S, Clapham DE. Primary cilia are specialized calcium signalling organelles. Nature. 2013;504(7479):311–4.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Ma M, Tian X, Igarashi P, Pazour GJ, Somlo S. Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease. Nat Genet. 2013;45(9):1004–12.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Bakeberg JL, Tammachote R, Woollard JR, Hogan MC, Tuan H, van Deursen JM, et al. Epitope-tagged Pkhd1 tracks the processing, secretion, and localization of fibrocystin. J Am Soc Nephrol. 2011;22(12):2266–77.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Chebib FT, Sussman CR, Wang X, Harris PC, Torres VE. Vasopressin and disruption of calcium signalling in polycystic kidney disease. Nat Rev Nephrol. 2015;11(8):451–64.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Yuan S, Zhao L, Brueckner M, Sun Z. Intraciliary calcium oscillations initiate vertebrate left-right asymmetry. Curr Biol. 2015;25(5):556–67.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Fischer E, Legue E, Doyen A, Nato F, Nicolas JF, Torres V, et al. Defective planar cell polarity in polycystic kidney disease. Nat Genet. 2006;38(1):21–3.PubMedCrossRefPubMedCentralGoogle Scholar
  143. 143.
    Nishio S, Tian X, Gallagher AR, Yu Z, Patel V, Igarashi P, et al. Loss of oriented cell division does not initiate cyst formation. J Am Soc Nephrol. 2010;21(2):295–302.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Bhunia AK, Piontek K, Boletta A, Liu L, Qian F, Xu PN, et al. PKD1 induces p2waf1 and regulation of the cell cycle via direct activation of the JAK-STAT signaling pathway in a process requiring PKD2. Cell. 2002;109(2):157–68.PubMedCrossRefPubMedCentralGoogle Scholar
  145. 145.
    Streets AJ, Newby LJ, O'Hare MJ, Bukanov NO, Ibraghimov-Beskrovnaya O, Ong AC. Functional analysis of PKD1 transgenic lines reveals a direct role for polycystin-1 in mediating cell-cell adhesion. J Am Soc Nephrol. 2003;14:1804–15.PubMedCrossRefPubMedCentralGoogle Scholar
  146. 146.
    Field S, Riley KL, Grimes DT, Hilton H, Simon M, Powles-Glover N, et al. Pkd1l1 establishes left-right asymmetry and physically interacts with Pkd2. Development. 2011;138(6):1131–42.PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Kamura K, Kobayashi D, Uehara Y, Koshida S, Iijima N, Kudo A, et al. Pkd1l1 complexes with PKD2 on motile cilia and functions to establish the left-right axis. Development. 2011;138(6):1121–9.PubMedCrossRefPubMedCentralGoogle Scholar
  148. 148.
    Sutton KA, Jungnickel MK, Ward CJ, Harris PC, Florman HM. Functional characterization of PKDREJ, a male germ cell-restricted polycystin. J Cell Physiol. 2006;209(2):493–500.PubMedCrossRefPubMedCentralGoogle Scholar
  149. 149.
    Chen Y, Zhang Z, Lv XY, Wang YD, Hu ZG, Sun H, et al. Expression of Pkd2l2 in testis is implicated in spermatogenesis. Biol Pharm Bull. 2008;31(8):1496–500.PubMedCrossRefPubMedCentralGoogle Scholar
  150. 150.
    Ishimaru Y, Inada H, Kubota M, Zhuang H, Tominaga M, Matsunami H. Transient receptor potential family members PKD1L3 and PKD2L1 form a candidate sour taste receptor. Proc Natl Acad Sci U S A. 2006;103(33):12569–74.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Mackenzie FE, Romero R, Williams D, Gillingwater T, Hilton H, Dick J, et al. Upregulation of PKD1L2 provokes a complex neuromuscular disease in the mouse. Hum Mol Genet. 2009;18(19):3553–66.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Guay-Woodford LM, Bissler JJ, Braun MC, Bockenhauer D, Cadnapaphornchai MA, Dell KM, et al. Consensus expert recommendations for the diagnosis and management of autosomal recessive polycystic kidney disease: report of an international conference. J Pediatr. 2014;165(3):611–7.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Shneider BL, Magid MS. Liver disease in autosomal recessive polycystic kidney disease. Pediatr Transplant. 2005;9(5):634–9.PubMedCrossRefPubMedCentralGoogle Scholar
  154. 154.
    Adeva M, El-Youssef M, Rossetti S, Kamath PS, Kubly V, Consugar M, et al. Clinical and molecular characterization defines a broadened spectrum of autosomal recessive polycystic kidney disease (ARPKD). Medicine. 2006;85(1):1–21.PubMedCrossRefPubMedCentralGoogle Scholar
  155. 155.
    Zerres K, Mücher G, Bachner L, Deschennes G, Eggermann T, Kääriäinen H, et al. Mapping of the gene for autosomal recessive polycystic kidney disease (ARPKD) to chromosome 6p21-cen. Nat Genet. 1994;7:429–32.PubMedCrossRefPubMedCentralGoogle Scholar
  156. 156.
    Guay-Woodford LM, Muecher G, Hopkins SD, Avner ED, Germino GG, Guillot AP, 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;56:1101–7.PubMedPubMedCentralGoogle Scholar
  157. 157.
    Lens XM, Onuchic LF, Wu G, Hayashi T, Daoust M, Mochizuki T, et al. An integrated genetic and physical map of the autosomal recessive polycystic kidney disease region. Genomics. 1997;41(3):463–6.PubMedCrossRefPubMedCentralGoogle Scholar
  158. 158.
    Mücher G, Becker J, Knapp M, Büttner R, Moser M, Rudnik-Schöneborn S, et al. Fine mapping of the autosomal recessive polycystic kidney disease locus (PKHD1) and the genes MUT, RDS, CSNK2β, and GSTA1 at 6p21.2-p12. Genomics. 1998;48:40–5.PubMedCrossRefPubMedCentralGoogle Scholar
  159. 159.
    Park JH, Dixit MP, Onuchic LF, Wu G, Goncharuk AN, Kneitz S, et al. A 1-Mb BAC/PAC-based physical map of the autosomal recessive polycystic kidney disease gene (PKHD1) region on chromosome 6. Genomics. 1999;57(2):249–55.PubMedCrossRefPubMedCentralGoogle Scholar
  160. 160.
    Ward CJ, Hogan MC, Rossetti S, Walker D, Sneddon T, Wang X, et al. The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein. Nat Genet. 2002;30(3):259–69.PubMedCrossRefPubMedCentralGoogle Scholar
  161. 161.
    Onuchic LF, Furu L, Nagasawa Y, Hou X, Eggermann T, Ren Z, 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(5):1305–17.PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Bergmann C, Frank V, Kupper F, Schmidt C, Senderek J, Zerres K. Functional analysis of PKHD1 splicing in autosomal recessive polycystic kidney disease. J Hum Genet. 2006;51(9):788–93.PubMedCrossRefPubMedCentralGoogle Scholar
  163. 163.
    Boddu R, Yang C, O'Connor AK, Hendrickson RC, Boone B, Cui X, et al. Intragenic motifs regulate the transcriptional complexity of Pkhd1/PKHD1. J Mol Med (Berl). 2014;92(10):1045–56.PubMedCentralCrossRefGoogle Scholar
  164. 164.
    Frank V, Zerres K, Bergmann C. Transcriptional complexity in autosomal recessive polycystic kidney disease. Clin J Am Soc Nephrol. 2014;9(10):1729–36.PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Bergmann C, Senderek J, Sedlacek B, Pegiazoglou I, Puglia P, Eggermann T, et al. Spectrum of mutations in the gene for autosomal recessive polycystic kidney disease (ARPKD/PKHD1). J Am Soc Nephrol. 2003;14(1):76–89.PubMedCrossRefPubMedCentralGoogle Scholar
  166. 166.
    Rossetti S, Torra R, Coto E, Consugar M, Kubly V, Malaga S, et al. A complete mutation screen of PKHD1 in autosomal recessive polycystic kidney pedigrees. Kidney Int. 2003;64:391–403.PubMedCrossRefPubMedCentralGoogle Scholar
  167. 167.
    Furu L, Onuchic LF, Gharavi AG, Hou X, Esquivel EL, Nagasawa Y, et al. Milder presentation of recessive polycystic kidney disease requires presence of amino acid substitution mutations. J Am Soc Nephrol. 2003;14:2004–14.PubMedCrossRefPubMedCentralGoogle Scholar
  168. 168.
    Sharp AM, Messiaen LM, Page G, Antignac C, Gubler MC, Onuchic LF, et al. Comprehensive genomic analysis of PKHD1 mutations in ARPKD cohorts. J Med Genet. 2005;42(4):336–49.PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Bergmann C, Kupper F, Dornia C, Schneider F, Senderek J, Zerres K. Algorithm for efficient PKHD1 mutation screening in autosomal recessive polycystic kidney disease (ARPKD). Hum Mutat. 2005;25(3):225–31.PubMedCrossRefPubMedCentralGoogle Scholar
  170. 170.
    Consugar MB, Anderson SA, Rossetti S, Pankratz VS, Ward CJ, Torra R, et al. Haplotype analysis improves molecular diagnostics of autosomal recessive polycystic kidney disease. Am J Kidney Dis. 2005;45:77–87.PubMedCrossRefPubMedCentralGoogle Scholar
  171. 171.
    Krall P, Pineda C, Ruiz P, Ejarque L, Vendrell T, Camacho JA, et al. Cost-effective PKHD1 genetic testing for autosomal recessive polycystic kidney disease. Pediatr Nephrol. 2014;29(2):223–34.PubMedCrossRefPubMedCentralGoogle Scholar
  172. 172.
    Hartung EA, Guay-Woodford LM. Autosomal recessive polycystic kidney disease: a hepatorenal fibrocystic disorder with pleiotropic effects. Pediatrics. 2014;134(3):e833–45.PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Tavira B, Gomez J, Malaga S, Santos F, Fernandez-Aracama J, Alonso B, et al. A labor and cost effective next generation sequencing of PKHD1 in autosomal recessive polycystic kidney disease patients. Gene. 2015;561(1):165–9.PubMedCrossRefPubMedCentralGoogle Scholar
  174. 174.
    Eisenberger T, Decker C, Hiersche M, Hamann RC, Decker E, Neuber S, et al. An efficient and comprehensive strategy for genetic diagnostics of polycystic kidney disease. PLoS One. 2015;10(2):e0116680.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Denamur E, Delezoide AL, Alberti C, Bourillon A, Gubler MC, Bouvier R, et al. Genotype-phenotype correlations in fetuses and neonates with autosomal recessive polycystic kidney disease. Kidney Int. 2010;77(4):350–8.PubMedCrossRefPubMedCentralGoogle Scholar
  176. 176.
    Bergmann C, Senderek J, Windelen E, Kupper F, Middeldorf I, Schneider F, et al. Clinical consequences of PKHD1 mutations in 164 patients with autosomal-recessive polycystic kidney disease (ARPKD). Kidney Int. 2005;67(3):829–48.PubMedCrossRefPubMedCentralGoogle Scholar
  177. 177.
    Ebner K, Feldkoetter M, Ariceta G, Bergmann C, Buettner R, Doyon A, et al. Rationale, design and objectives of ARegPKD, a European ARPKD registry study. BMC Nephrol. 2015;16:22.PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Sweeney WE, Avner ED. Polycystic kidney disease, autosomal recessive. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong CT, et al., editors. GeneReviews(R). Seattle: University of Washington, Seattle; 2014. Internet. http://www.ncbi.nlm.nih.gov/pubmed/20301501.Google Scholar
  179. 179.
    Gunay-Aygun M, Turkbey BI, Bryant J, Daryanani KT, Gerstein MT, Piwnica-Worms K, Choyke P, Heller T, Gahl WA. Hepatorenal findings in obligate heterozygotes for autosomal recessive polycystic kidney disease. Mol Genet Metab. 2011;104:677–81.PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    Zvereff V, Yao S, Ramsey J, Mikhail FM, Vijzelaar R, Messiaen L. Identification of PKHD1 multiexon deletions using multiplex ligation-dependent probe amplification and quantitative polymerase chain reaction. Genet Test Mol Biomarkers. 2010;14(4):505–10.PubMedCrossRefPubMedCentralGoogle Scholar
  181. 181.
    Gunay-Aygun M, Parisi MA, Doherty D, Tuchman M, Tsilou E, Kleiner DE, et al. MKS3-related ciliopathy with features of autosomal recessive polycystic kidney disease, nephronophthisis, and Joubert Syndrome. J Pediatr. 2009;155(3):386–92 e1.PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Bergmann C. ARPKD and early manifestations of ADPKD: the original polycystic kidney disease and phenocopies. Pediatr Nephrol. 2015;30:15–30.PubMedCrossRefPubMedCentralGoogle Scholar
  183. 183.
    Gigarel N, Frydman N, Burlet P, Kerbrat V, Tachdjian G, Fanchin R, et al. Preimplantation genetic diagnosis for autosomal recessive polycystic kidney disease. Reprod Biomed Online. 2008;16(1):152–8.PubMedCrossRefPubMedCentralGoogle Scholar
  184. 184.
    Lau EC, Janson MM, Roesler MR, Avner ED, Strawn EY, Bick DP. Birth of a healthy infant following preimplantation PKHD1 haplotyping for autosomal recessive polycystic kidney disease using multiple displacement amplification. J Assist Reprod Genet. 2010;27(7):397–407.PubMedPubMedCentralCrossRefGoogle Scholar
  185. 185.
    Gattone VH 2nd, Wang X, Harris PC, Torres VE. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nature Med. 2003;9(10):1323–6.PubMedCrossRefPubMedCentralGoogle Scholar
  186. 186.
    Lager DJ, Qian Q, Bengal RJ, Ishibashi M, Torres VE. The pck rat: a new model that resembles human autosomal dominant polycystic kidney and liver disease. Kidney Int. 2001;59(1):126–36.PubMedCrossRefPubMedCentralGoogle Scholar
  187. 187.
    Woollard JR, Punyashtiti R, Richardson S, Masyuk TV, Whelan S, Huang BQ, et al. A mouse model of autosomal recessive polycystic kidney disease with biliary duct and proximal tubule dilatation. Kidney Int. 2007;72(3):328–36.PubMedCrossRefPubMedCentralGoogle Scholar
  188. 188.
    Garcia-Gonzalez MA, Menezes LF, Piontek KB, Kaimori J, Huso DL, Watnick T, et al. Genetic interaction studies link autosomal dominant and recessive polycystic kidney disease in a common pathway. Hum Mol Genet. 2007;16(16):1940–50.PubMedPubMedCentralCrossRefGoogle Scholar
  189. 189.
    Gallagher AR, Esquivel EL, Briere TS, Tian X, Mitobe M, Menezes LF, et al. Biliary and pancreatic dysgenesis in mice harboring a mutation in Pkhd1. Am J Pathol. 2008;172(2):417–29.PubMedPubMedCentralCrossRefGoogle Scholar
  190. 190.
    Williams SS, Cobo-Stark P, James LR, Somlo S, Igarashi P. Kidney cysts, pancreatic cysts, and biliary disease in a mouse model of autosomal recessive polycystic kidney disease. Pediatr Nephrol. 2008;23(5):733–41.PubMedCrossRefPubMedCentralGoogle Scholar
  191. 191.
    Masyuk TV, Huang BQ, Ward CJ, Masyuk AI, Yuan D, Splinter PL, et al. Defects in cholangiocyte fibrocystin expression and ciliary structure in the PCK rat. Gastroenterology. 2003;125:1303–10.PubMedCrossRefPubMedCentralGoogle Scholar
  192. 192.
    Follit JA, Li L, Vucica Y, Pazour GJ. The cytoplasmic tail of fibrocystin contains a ciliary targeting sequence. J Cell Biol. 2010;188:21–8.PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    He QY, Liu XH, Li Q, Studholme DJ, Li XW, Liang SP. G8: a novel domain associated with polycystic kidney disease and non-syndromic hearing loss. Bioinformatics. 2006;22(18):2189–91.PubMedCrossRefPubMedCentralGoogle Scholar
  194. 194.
    Rigden DJ, Mello LV, Galperin MY. The PA14 domain, a conserved all β−domain in bacterial toxins, enzymes, adhesins and signaling molecules. Trends Biochem Sci. 2004;29(7):335–9.PubMedCrossRefPubMedCentralGoogle Scholar
  195. 195.
    Kaimori JY, Nagasawa Y, Menezes LF, Garcia-Gonzalez MA, Deng J, Imai E, et al. Polyductin undergoes notch-like processing and regulated release from primary cilia. Hum Mol Genet. 2007;16(8):942–56.PubMedPubMedCentralCrossRefGoogle Scholar
  196. 196.
    Hiesberger T, Gourley E, Erickson A, Koulen P, Ward CJ, Masyuk TV, et al. Proteolytic cleavage and nuclear translocation of fibrocystin is regulated by intracellular Ca2+ and activation of protein kinase C. J Biol Chem. 2006;281(45):34357–64.PubMedCrossRefPubMedCentralGoogle Scholar
  197. 197.
    Williams SS, Cobo-Stark P, Hajarnis S, Aboudehen K, Shao X, Richardson JA, et al. Tissue-specific regulation of the mouse Pkhd1 (ARPKD) gene promoter. Am J Physiol Renal Physiol. 2014;307(3):F356–68.PubMedPubMedCentralCrossRefGoogle Scholar
  198. 198.
    Ward CJ, Yuan D, Masyuk TV, Wang X, Punyashthiti R, Whelan S, et al. Cellular and subcellular localization of the ARPKD protein; fibrocystin is expressed on primary cilia. Hum Mol Genet. 2003;12:2703–10.PubMedCrossRefPubMedCentralGoogle Scholar
  199. 199.
    Wang S, Luo Y, Wilson PD, Witman GB, Zhou J. The autosomal recessive polycystic kidney disease protein is localized to primary cilia, with concentration in the basal body area. J Am Soc Nephrol. 2004;15(3):592–602.PubMedCrossRefPubMedCentralGoogle Scholar
  200. 200.
    Zhang J, Wu M, Wang S, Shah JV, Wilson PD, Zhou J. Polycystic kidney disease protein fibrocystin localizes to the mitotic spindle and regulates spindle bipolarity. Hum Mol Genet. 2010;19(17):3306–19.PubMedPubMedCentralCrossRefGoogle Scholar
  201. 201.
    Wang S, Zhang J, Nauli SM, Li X, Starremans PG, Luo Y, et al. Fibrocystin/polyductin, found in the same protein complex with polycystin-2, regulates calcium responses in kidney epithelia. Mol Cell Biol. 2007;27(8):3241–52.PubMedPubMedCentralCrossRefGoogle Scholar
  202. 202.
    Kim I, Fu Y, Hui K, Moeckel G, Mai W, Li C, et al. Fibrocystin/polyductin modulates renal tubular formation by regulating polycystin-2 expression and function. J Am Soc Nephrol. 2008;19(3):455–68.PubMedPubMedCentralCrossRefGoogle Scholar
  203. 203.
    Hogan MC, Griffin MD, Rossetti S, Torres VE, Ward CJ, Harris PC. PKHDL1, a homolog of the autosomal recessive polycystic kidney disease gene, encodes a receptor with inducible T lymphocyte expression. Hum Mol Genet. 2003;12:685–9.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of NephrologyEuropean University of BrittanyBrestFrance
  2. 2.Division of Nephrology and HypertensionMayo ClinicRochesterUS

Personalised recommendations