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Genetics of Fibrocystic Diseases of the Liver and Molecular Approaches to Therapy

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Fibrocystic Diseases of the Liver

Part of the book series: Clinical Gastroenterology ((CG))

Summary

Congenital hepatic fibrosis (CHF), Caroli’s disease (CD), and polycystic liver disease (PLD) are the three major descriptive categories of fibrocystic liver disease. Caroli’s syndrome (CS) and CD probably represent different presentations of the same continuum. CS refers to CD in association with CHF. CHF/CS and PLD are often part of multisystem disorders associated with fibrocystic renal involvement. These are collectively referred to as “ciliopathies,” since the abnormal proteins involved function on the primary cilium or its basal body. The inheritance pattern of CHF/CS is autosomal recessive, with rare exceptions such as the CHF associated with X-linked oral-facial-digital syndrome type 1. The inheritance pattern of PLD is autosomal dominant; the majority of patients have autosomal dominant polycystic kidney disease (ADPKD) caused by mutations in the PKD1 or PKD2 genes. Autosomal dominant polycystic liver disease (ADPLD), in which PLD is not associated with renal cysts, refers to a genetically distinct entity caused by mutations in the PRKCSH or SEC63 genes. CHF/CS most commonly presents in association with autosomal recessive polycystic kidney disease (ARPKD) caused by mutations in the PKHD1 gene. Multisystem syndromes associated with CHF/CS include Meckel, Bardet–Biedl, and Joubert syndromes and related cerebello-hepatorenal syndromes, renal-hepatic-pancreatic-dysplasia, and ciliary skeletal dysplasias such as Jeune’s chondrodysplasia. Many syndromic ciliopathies display marked genotypic heterogeneity with multiple different genes causing the same disease. This chapter will review the molecular genetic bases of these disorders and provide an overview of novel targeted therapies.

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References

  1. Caroli J. Diseases of intrahepatic bile ducts. Isr J Med Sci 1968;4, 21–35.

    CAS  PubMed  Google Scholar 

  2. Caroli J. Diseases of the intrahepatic biliary tree. Clin Gastroenterol 1973;2, 147–161.

    CAS  PubMed  Google Scholar 

  3. Kerkar NK, Norton K, Suchy FJ. The hepatic fibrocystic diseases. Clin Liver Dis 2006;10, 55–71.

    PubMed  Google Scholar 

  4. Tahvanainen E, Tahvanainen P, Kääriäinen H, Höckerstedt K. Polycystic liver and kidney diseases. Ann Med 2005;37, 546–555.

    CAS  PubMed  Google Scholar 

  5. Morgan DE, Lockhart ME, Canon CL et al. Polycystic liver disease: Multimodality imaging for complications and transplant evaluation. Radiographics 2006;26, 1655–1668.

    PubMed  Google Scholar 

  6. Drenth JP, Martina JA, van de Kerkhof R et al. Polycystic liver disease is a disorder of cotranslational protein processing. Trends Mol Med 2005;11, 37–42.

    CAS  PubMed  Google Scholar 

  7. Prattichizzo C, Macca M, Novelli V et al. Mutational spectrum of the oral-facial-digital type I syndrome: A study on a large collection of patients. Hum Mutat 2008;29, 1237–1246.

    CAS  PubMed  Google Scholar 

  8. Gunay-Aygun M, Gahl WA, Heller T. Congenital hepatic fibrosis overview: In GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997–2008. Available at http://www.genetests.org. 2008.

  9. Zerres K, Rudnik-Schöneborn S, Deget F et al. Autosomal recessive polycystic kidney disease in 115 children: Clinical presentation, course and influence of gender. Arbeitsgemeinschaft fur Padiatrische, Nephrologie. Acta Paediatr 1996;85, 437–445.

    CAS  Google Scholar 

  10. Gunay-Aygun M, Avner ED, Bacallao RL et al. Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis: Summary statement of a first National Institutes of Health/Office of Rare Diseases conference. J Pediatr 2006;149, 159–164.

    PubMed  Google Scholar 

  11. Guay-Woodford LM, Desmond RA. Autosomal recessive polycystic kidney disease: The clinical experience in North America. Pediatrics 2003;111(5 Pt 1), 1072–1080.

    PubMed  Google Scholar 

  12. Fraser FC, Lytwyn A. Spectrum of anomalies in the Meckel syndrome, or: “Maybe there is a malformation syndrome with at least one constant anomaly”. Am J Med Genet 1981;9, 67–73.

    CAS  PubMed  Google Scholar 

  13. Chen CP. Meckel syndrome: Genetics, perinatal findings, and differential diagnosis. Taiwan J Obstet Gynecol 2007;46, 9–14.

    PubMed  Google Scholar 

  14. Uemura T, Sanchez EQ, Ikegami T et al. Successful combined liver and kidney transplant for COACH syndrome and 5-yr follow-up. Clin Transplant 2005;19, 717–720.

    PubMed  Google Scholar 

  15. Satran D, Pierpont ME, Dobyns DB. Cerebello-oculo-renal syndromes including Arima, Senior-Loken and COACH syndromes: More than just variants of Joubert syndrome. Am J Med Genet 1999;86, 459–469.

    CAS  PubMed  Google Scholar 

  16. Bernstein J, Chandra M, Creswell J et al. Renal-hepatic-pancreatic dysplasia: A syndrome reconsidered. Am J Med Genet 1987;26, 391–403.

    CAS  PubMed  Google Scholar 

  17. White SM, Hurst JA, Hamoda H et al. Renal-hepatic-pancreatic dysplasia: A broad entity. Am J Med Genet 2000;95, 399–400.

    CAS  PubMed  Google Scholar 

  18. Torra R, Alós L, Ramos J, Estivill X. Renal-hepatic-pancreatic dysplasia: An autosomal recessive malformation. J Med Genet 1996;33, 409–412.

    CAS  PubMed  Google Scholar 

  19. Parisi MA, Doherty D, Chance PF, Glass IA. Joubert syndrome (and related disorders) (OMIM 213300). Eur J Hum Genet 2007;15, 511–521.

    CAS  PubMed  Google Scholar 

  20. Lewis SM, Roberts EA, Marcon MA et al. Joubert syndrome with congenital hepatic fibrosis: An entity in the spectrum of oculo-encephalo-hepato-renal disorders. Am J Med Genet 1994;52, 419–426.

    CAS  PubMed  Google Scholar 

  21. Silverstein DM, Zacharowicz L, Edelman M et al. Joubert syndrome associated with multicystic kidney disease and hepatic fibrosis. Pediatr Nephrol 1997;11, 746–749.

    CAS  PubMed  Google Scholar 

  22. Nakamura F, Sasaki H, Kajihara H, Yamanoue M. Laurence-Moon-Biedl syndrome accompanied by congenital hepatic fibrosis. J Gastroenterol Hepatol 1990;5, 206–210.

    CAS  PubMed  Google Scholar 

  23. Pagon RA, Haas JE, Bunt AH, Rodaway KA. Hepatic involvement in the Bardet-Biedl syndrome. Am J Med Genet 1982;13, 373–381.

    CAS  PubMed  Google Scholar 

  24. Toprak O, Uzum A, Cirit M et al. Oral-facial-digital syndrome type 1, Caroli’s disease and cystic renal disease. Nephrol Dial Transplant 2006;21, 1705–1709.

    PubMed  Google Scholar 

  25. Gurrieri F, Franco B, Toriello H, Neri G. Oral-facial-digital syndromes: Review and diagnostic guidelines. Am J Med Genet A 2007;143A, 3314–3323.

    PubMed  Google Scholar 

  26. Thauvin-Robinet C, Cossée M, Cormier-Daire V et al. Clinical, molecular, and genotype-phenotype correlation studies from 25 cases of oral-facial-digital syndrome type 1: A French and Belgian collaborative study. J Med Genet 2006;43, 54–61.

    CAS  PubMed  Google Scholar 

  27. Yerian LM, Brady L, Hart J. Hepatic manifestations of Jeune syndrome (asphyxiating thoracic dystrophy). Semin Liver Dis 2003;23, 195–200.

    PubMed  Google Scholar 

  28. Labrune P, Fabre M, Trioche P et al. Jeune syndrome and liver disease: Report of three cases treated with ursodeoxycholic acid. Am J Med Genet 1999;87, 324–328.

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  30. Fliegauf M, Benzing T, Omran H. When cilia go bad: Cilia defects and ciliopathies. Nat Rev Mol Cell Biol 2007;8, 880–893.

    CAS  PubMed  Google Scholar 

  31. Badano JL, Mitsuma N, Beales PL, Katsanis N. The ciliopathies: An emerging class of human genetic disorders. Annu Rev Genomics Hum Genet 2006;7, 125–148.

    CAS  PubMed  Google Scholar 

  32. Masyuk AI, Masyuk TV, LaRusso NF. Cholangiocyte primary cilia in liver health and disease. Dev Dyn 2008;237, 2007–2012.

    CAS  PubMed  Google Scholar 

  33. Harris PCTVE, Polycystic Kidney Disease, Autosomal Dominant. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997–2008. Available at http://www.genetests.org. 2008.

  34. Shedda S, Robertson A. Caroli’s syndrome and adult polycystic kidney disease. ANZ J Surg 2007;77, 292–294.

    PubMed  Google Scholar 

  35. The European Polycystic Kidney Disease Consortium. The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. Cell 1994;78, 725.

    Google Scholar 

  36. Hughes J, Ward CJ, Peral B et al. The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains. Nat Genet 1995;10, 151–160.

    CAS  PubMed  Google Scholar 

  37. Mochizuki T, Wu G, Hayashi T et al. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 1996;272, 1339–1342.

    CAS  PubMed  Google Scholar 

  38. Torra R, Badenas C, Darnell A et al. Linkage, clinical features, and prognosis of autosomal dominant polycystic kidney disease types 1 and 2. J Am Soc Nephrol 1996;7, 2142–2151.

    CAS  PubMed  Google Scholar 

  39. Reeders ST, Breuning MH, Davies KE et al. A highly polymorphic DNA marker linked to adult polycystic kidney disease on chromosome 16. Nature 1985;317, 542–544.

    CAS  PubMed  Google Scholar 

  40. Rossetti S, Burton S, Strmecki L et al. The position of the polycystic kidney disease 1 (PKD1) gene mutation correlates with the severity of renal disease. J Am Soc Nephrol 2002;13, 1230–1237.

    CAS  PubMed  Google Scholar 

  41. Magistroni R, He N, Wang K et al. Genotype-renal function correlation in type 2 autosomal dominant polycystic kidney disease. J Am Soc Nephrol 2003;14, 1164–1174.

    PubMed  Google Scholar 

  42. Rossetti S, Chauveau D, Kubly V et al. Association of mutation position in polycystic kidney disease 1 (PKD1) gene and development of a vascular phenotype. Lancet 2003;361, 2196–2201.

    CAS  PubMed  Google Scholar 

  43. Kimberling WJ, Kumar S, Gabow PA et al. Autosomal dominant polycystic kidney disease: Localization of the second gene to chromosome 4q13-q23. Genomics 1993;18, 467–472.

    CAS  PubMed  Google Scholar 

  44. Rossetti S, Consugar MB, Chapman AB et al. Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 2007;18, 2143–2160.

    CAS  PubMed  Google Scholar 

  45. Burn TC, Connors TD, Dackowski WR et al. Analysis of the genomic sequence for the autosomal dominant polycystic kidney disease (PKD1) gene predicts the presence of a leucine-rich repeat. The American PKD1 Consortium (APKD1 Consortium). Hum Mol Genet 1995;4, 575–582.

    CAS  PubMed  Google Scholar 

  46. Qian F, Boletta A, Bhunia 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 USA 2002;99, 16981–16986.

    CAS  PubMed  Google Scholar 

  47. Chauvet V, Tian X, Husson H et al. Mechanical stimuli induce cleavage and nuclear translocation of the polycystin-1 C terminus. J Clin Invest 2004;114, 1433–1443.

    CAS  PubMed  Google Scholar 

  48. Ibraghimov-Beskrovnaya O, Bukanov N. Polycystic kidney diseases: From molecular discoveries to targeted therapeutic strategies. Cell Mol Life Sci 2008;65, 605–619.

    CAS  PubMed  Google Scholar 

  49. Nauli SM, Alenghat FJ, Luo Y et al. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet 2003;33, 129–137.

    CAS  PubMed  Google Scholar 

  50. Ward CJ, Hogan MC, Rossetti S et al. The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein. Nat Genet 2002;30, 259–269.

    PubMed  Google Scholar 

  51. Onuchic LF, Furu L, Nagasawa Y et al. PKHD1, the polycystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple immunoglobulin-like plexin-transcription-factor domains and parallel beta-helix 1 repeats. Am J Hum Genet 2002;70, 1305–1317.

    CAS  PubMed  Google Scholar 

  52. Sweeney WE, Jr, Avner ED. Molecular and cellular pathophysiology of autosomal recessive polycystic kidney disease (ARPKD). Cell Tissue Res 2006;326, 671–685.

    CAS  PubMed  Google Scholar 

  53. Bergmann C, Senderek J, Küpper F et al. PKHD1 mutations in autosomal recessive polycystic kidney disease (ARPKD). Hum Mutat 2004;23, 453–463.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  56. Wu Y, Dai XQ, Li Q et al. Kinesin-2 mediates physical and functional interactions between polycystin-2 and fibrocystin. Hum Mol Genet 2006;15, 3280–3292.

    CAS  PubMed  Google Scholar 

  57. Tahvanainen P, Tahvanainen E, Reijonen H et al. Polycystic liver disease is genetically heterogeneous: Clinical and linkage studies in eight Finnish families. J Hepatol 2003;38, 39–43.

    CAS  PubMed  Google Scholar 

  58. Drenth JP, Temorsche RH, Smink R et al. Germline mutations in PRKCSH are associated with autosomal dominant polycystic liver disease. Nat Genet 2003;33, 345–347.

    CAS  PubMed  Google Scholar 

  59. Li A, Davila S, Furu L et al. Mutations in PRKCSH cause isolated autosomal dominant polycystic liver disease. Am J Hum Genet 2003;72, 691–703.

    CAS  PubMed  Google Scholar 

  60. Davila S, Furu L, Gharavi AG et al. Mutations in SEC63 cause autosomal dominant polycystic liver disease. Nat Genet 2004;36, 575–577.

    CAS  PubMed  Google Scholar 

  61. Waanders E, te Morsche RH, de Man RA et al. Extensive mutational analysis of PRKCSH and SEC63 broadens the spectrum of polycystic liver disease. Hum Mutat 2006;27, 830.

    PubMed  Google Scholar 

  62. Drenth JP, Martina JA, Te Morsche RH et al. Molecular characterization of hepatocystin, the protein that is defective in autosomal dominant polycystic liver disease. Gastroenterology 2004;126, 1819–1827.

    CAS  PubMed  Google Scholar 

  63. Trombetta ES, Simons JF, Helenius A. Endoplasmic reticulum glucosidase II is composed of a catalytic subunit, conserved from yeast to mammals, and a tightly bound noncatalytic HDEL-containing subunit. J Biol Chem 1996;271, 27509–27516.

    CAS  PubMed  Google Scholar 

  64. Arendt CW, Ostergaard HL. Two distinct domains of the beta-subunit of glucosidase II interact with the catalytic alpha-subunit. Glycobiology 2000;10, 487–492.

    CAS  PubMed  Google Scholar 

  65. Waanders E, Croes HJ, Maass CN et al. Cysts of PRKCSH mutated polycystic liver disease patients lack hepatocystin but express Sec63p. Histochem Cell Biol 2008;129, 301–310.

    CAS  PubMed  Google Scholar 

  66. Smith UM, Consugar M, Tee LJ et al. The transmembrane protein meckelin (MKS3) is mutated in Meckel–Gruber syndrome and the wpk rat. Nat Genet 2006;38, 191–196.

    CAS  PubMed  Google Scholar 

  67. Kyttälä M, Tallila J, Salonen R et al. MKS1, encoding a component of the flagellar apparatus basal body proteome, is mutated in Meckel syndrome. Nat Genet 2006;38, 155–157.

    PubMed  Google Scholar 

  68. Baala L, Audollent S, Martinovic J et al. Pleiotropic effects of CEP290 (NPHP6) mutations extend to Meckel syndrome. Am J Hum Genet 2007;81, 170–179.

    CAS  PubMed  Google Scholar 

  69. Delous M, Baala L, Salomon R et al. The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nat Genet 2007;39, 875–881.

    CAS  PubMed  Google Scholar 

  70. Tallila J, Jakkula E, Peltonen L et al. Identification of CC2D2A as a Meckel syndrome gene adds an important piece to the ciliopathy puzzle. Am J Hum Genet 2008;82, 1361–1367.

    CAS  PubMed  Google Scholar 

  71. Frank V, den Hollander AI, Brüchle NO et al. Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel–Gruber syndrome. Hum Mutat 2008;29, 45–52.

    CAS  PubMed  Google Scholar 

  72. Dawe HR, Smith UM, Cullinane AR et al. The Meckel–Gruber Syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation. Hum Mol Genet 2007;16, 173–186.

    CAS  PubMed  Google Scholar 

  73. Pedersen LB, Veland IR, Schrøder JM, Christensen ST. Assembly of primary cilia. Dev Dyn 2008;237, 1993–2006.

    CAS  PubMed  Google Scholar 

  74. Khaddour R, Smith U, Baala L et al. Spectrum of MKS1 and MKS3 mutations in Meckel syndrome: A genotype-phenotype correlation. Mutation in brief #960. Online. Hum Mutat 2007;28, 523–524.

    Google Scholar 

  75. Baala L, Romano S, Khaddour R et al. The Meckel–Gruber syndrome gene, MKS3, is mutated in Joubert syndrome. Am J Hum Genet 2007;80, 186–194.

    CAS  PubMed  Google Scholar 

  76. Consugar MB, Kubly VJ, Lager DJ et al. Molecular diagnostics of Meckel–Gruber syndrome highlights phenotypic differences between MKS1 and MKS3. Hum Genet 2007;121, 591–599.

    CAS  PubMed  Google Scholar 

  77. Roume J, Genin E, Cormier-Daire V et al. A gene for Meckel syndrome maps to chromosome 11q13. Am J Hum Genet 1998;63, 1095–1101.

    CAS  PubMed  Google Scholar 

  78. Valente EM, Brancati F, Dallapiccola B. Genotypes and phenotypes of Joubert syndrome and related disorders. Eur J Med Genet 2008;51, 1–23.

    PubMed  Google Scholar 

  79. Dixon-Salazar T, Silhavy JL, Marsh SE et al. Mutations in the AHI1 gene, encoding jouberin, cause Joubert syndrome with cortical polymicrogyria. Am J Hum Genet 2004;75, 979–987.

    CAS  PubMed  Google Scholar 

  80. Ferland RJ, Eyaid W, Collura RV et al. Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome. Nat Genet 2004;36, 1008–1013.

    CAS  PubMed  Google Scholar 

  81. Parisi MA, Doherty D, Eckert ML et al. AHI1 mutations cause both retinal dystrophy and renal cystic disease in Joubert syndrome. J Med Genet 2006;43, 334–339.

    CAS  PubMed  Google Scholar 

  82. Parisi MA, Bennett CL, Eckert ML et al. The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome. Am J Hum Genet 2004;75, 82–91.

    CAS  PubMed  Google Scholar 

  83. Hoefele J, Sudbrak R, Reinhardt R et al. Mutational analysis of the NPHP4 gene in 250 patients with nephronophthisis. Hum Mutat 2005;25, 411.

    PubMed  Google Scholar 

  84. Sayer JA, Otto EA, O’Toole JF et al. The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nat Genet 2006;38, 674–681.

    CAS  PubMed  Google Scholar 

  85. Kim J, Krishnaswami SR, Gleeson JG. CEP290 interacts with the centriolar satellite component PCM-1 and is required for Rab8 localization to the primary cilium. Hum Mol Genet 2008;17, 3796–3805; Epub 2008 Sep 4.

    CAS  PubMed  Google Scholar 

  86. Harris PC. Genetic complexity in Joubert syndrome and related disorders. Kidney Int 2007;72, 1421–1423.

    CAS  PubMed  Google Scholar 

  87. Ross AJand Beales PL, Bardet-Biedl In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997–2008. Available at http://www.genetests.org. 2007.

  88. Nachury MV, Loktev AV, Zhang Q et al. A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell 2007;129, 1201–1213.

    CAS  PubMed  Google Scholar 

  89. Beales PL. Lifting the lid on Pandora’s box: The Bardet-Biedl syndrome. Curr Opin Genet Dev 2005;15, 315–323.

    CAS  PubMed  Google Scholar 

  90. Mykytyn K, Nishimura DY, Searby CC et al. Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome, a complex human obesity syndrome. Nat Genet 2002;31, 435–438.

    CAS  PubMed  Google Scholar 

  91. Blacque OE, Reardon MJ, Li C et al. Loss of C. elegans BBS-7 and BBS-8 protein function results in cilia defects and compromised intraflagellar transport. Genes Dev 2004;18, 1630–1642.

    CAS  PubMed  Google Scholar 

  92. Nishimura DY, Searby CC, Carmi R et al. Positional cloning of a novel gene on chromosome 16q causing Bardet-Biedl syndrome (BBS2). Hum Mol Genet 2001;10, 865–874.

    CAS  PubMed  Google Scholar 

  93. Fan Y, Esmail MA, Ansley SJ et al. Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome. Nat Genet 2004;36, 989–993.

    CAS  PubMed  Google Scholar 

  94. Chiang AP, Nishimura D, Searby C et al. Comparative genomic analysis identifies an ADP-ribosylation factor-like gene as the cause of Bardet-Biedl syndrome (BBS3). Am J Hum Genet 2004;75, 475–484.

    CAS  PubMed  Google Scholar 

  95. Kim JC, Badano JL, Sibold S et al. The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression. Nat Genet 2004;36, 462–470.

    CAS  PubMed  Google Scholar 

  96. Mykytyn K, Braun T, Carmi R et al. Identification of the gene that, when mutated, causes the human obesity syndrome BBS4. Nat Genet 2001;28, 188–191.

    CAS  PubMed  Google Scholar 

  97. Li JB, Gerdes JM, Haycraft CJ et al. Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene. Cell 2004;117, 541–552.

    CAS  PubMed  Google Scholar 

  98. Stone DL, Slavotinek A, Bouffard GG et al. Mutation of a gene encoding a putative chaperonin causes McKusick-Kaufman syndrome. Nat Genet 2000;25, 79–82.

    CAS  PubMed  Google Scholar 

  99. Kim JC, Ou YY, Badano JL et al. MKKS/BBS6, a divergent chaperonin-like protein linked to the obesity disorder Bardet-Biedl syndrome, is a novel centrosomal component required for cytokinesis. J Cell Sci 2005;118, 1007–1020.

    CAS  PubMed  Google Scholar 

  100. Badano JL, Ansley SJ, Leitch CC et al. Identification of a novel Bardet-Biedl syndrome protein, BBS7, that shares structural features with BBS1 and BBS2. Am J Hum Genet 2003;72, 650–658.

    CAS  PubMed  Google Scholar 

  101. Ansley SJ, Badano JL, Blacque OE et al. Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome. Nature 2003;425, 628–633.

    CAS  PubMed  Google Scholar 

  102. Nishimura DY, Swiderski RE, Searby CC et al. Comparative genomics and gene expression analysis identifies BBS9, a new Bardet-Biedl syndrome gene. Am J Hum Genet 2005;77, 1021–1033.

    CAS  PubMed  Google Scholar 

  103. Stoetzel C, Laurier V, Davis EE et al. BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus. Nat Genet 2006;38, 521–524.

    CAS  PubMed  Google Scholar 

  104. Chiang AP, Beck JS, Yen HJ et al. Homozygosity mapping with SNP arrays identifies TRIM32, an E3 ubiquitin ligase, as a Bardet-Biedl syndrome gene (BBS11). Proc Natl Acad Sci USA 2006;103, 6287–6292.

    CAS  PubMed  Google Scholar 

  105. McDaniell R, Warthen DM, Sanchez-Lara PA et al. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet 2006;79, 169–173.

    CAS  PubMed  Google Scholar 

  106. Warthen DM, Moore EC, Kamath BM et al. Jagged1 (JAG1) mutations in Alagille syndrome: Increasing the mutation detection rate. Hum Mutat 2006;27, 436–443.

    CAS  PubMed  Google Scholar 

  107. Röpke A, Kujat A, Gräber M et al. Identification of 36 novel Jagged1 (JAG1) mutations in patients with Alagille syndrome. Hum Mutat 2003;21, 100.

    PubMed  Google Scholar 

  108. Hildebrandt F, Zhou W. Nephronophthisis-associated ciliopathies. J Am Soc Nephrol 2007;18, 1855–1871.

    CAS  PubMed  Google Scholar 

  109. Donaldson JC, Dise RS, Ritchie MD, Hanks SK. Nephrocystin-conserved domains involved in targeting to epithelial cell–cell junctions, interaction with filamins, and establishing cell polarity. J Biol Chem 2002;277, 29028–29035.

    CAS  PubMed  Google Scholar 

  110. Hildebrandt F, Otto E, Rensing C et al. A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1. Nat Genet 1997;17, 149–153.

    CAS  PubMed  Google Scholar 

  111. Donaldson JC, Dempsey PJ, Reddy S et al. Crk-associated substrate p130(Cas) interacts with nephrocystin and both proteins localize to cell–cell contacts of polarized epithelial cells. Exp Cell Res 2000;256, 168–178.

    CAS  PubMed  Google Scholar 

  112. Otto EA, Schermer B, Obara T et al. Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination. Nat Genet 2003;34, 413–420.

    CAS  PubMed  Google Scholar 

  113. Olbrich H, Fliegauf M, Hoefele J et al. Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis. Nat Genet 2003;34, 455–459.

    CAS  PubMed  Google Scholar 

  114. Otto E, Hoefele J, Ruf R et al. A gene mutated in nephronophthisis and retinitis pigmentosa encodes a novel protein, nephroretinin, conserved in evolution. Am J Hum Genet 2002;71, 1161–1167.

    CAS  PubMed  Google Scholar 

  115. Otto EA, Loeys B, Khanna H et al. Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin. Nat Genet 2005;37, 282–288.

    CAS  PubMed  Google Scholar 

  116. Beales PL, Bland E, Tobin JL et al. IFT80, which encodes a conserved intraflagellar transport protein, is mutated in Jeune asphyxiating thoracic dystrophy. Nat Genet 2007;39, 727–729.

    CAS  PubMed  Google Scholar 

  117. Thauvin-Robinet C, Franco B, Saugier-Veber P et al. Genomic deletions of OFD1 account for 23% of oral-facial-digital type 1 syndrome after negative DNA sequencing. Hum Mutat 2008.

    Google Scholar 

  118. Chapman AB. Approaches to testing new treatments in autosomal dominant polycystic kidney disease: Insights from the CRISP and HALT-PKD studies. Clin J Am Soc Nephrol 2008;3, 1197–1204.

    CAS  PubMed  Google Scholar 

  119. Masoumi A, Reed-Gitomer B, Kelleher C, Schrier RW. Potential pharmacological interventions in polycystic kidney disease. Drugs 2007;67, 2495–2510.

    CAS  PubMed  Google Scholar 

  120. Torres VE, Harris PC. Polycystic kidney disease: Genes, proteins, animal models, disease mechanisms and therapeutic opportunities. J Intern Med 2007;261, 17–31.

    CAS  PubMed  Google Scholar 

  121. Sweeney WE, Jr, von Vigier RO, Frost P, Avner ED. Src inhibition ameliorates polycystic kidney disease. J Am Soc Nephrol 2008;19, 1331–1341.

    CAS  PubMed  Google Scholar 

  122. Harris PC, Torres VE. Polycystic kidney disease. Annu Rev Med 2008; Oct 23 [Epub ahead of print].

    Google Scholar 

  123. Wilson PD. Polycystic kidney disease. N Engl J Med 2004;350, 151–164.

    Google Scholar 

  124. Torres VE, Harris PC. Mechanisms of disease: Autosomal dominant and recessive polycystic kidney diseases. Nat Clin Pract Nephrol 2006;2, 40–55.

    CAS  PubMed  Google Scholar 

  125. Torres VE. Cyclic AMP, at the hub of the cystic cycle. Kidney Int 2004;66, 1283–1285.

    PubMed  Google Scholar 

  126. Yamaguchi T, Nagao S, Wallace DP et al. Cyclic AMP activates B-Raf and ERK in cyst epithelial cells from autosomal-dominant polycystic kidneys. Kidney Int 2003;63, 1983–1994.

    CAS  PubMed  Google Scholar 

  127. Orellana SA, Sweeney WE, Neff CD, Avner ED. Epidermal growth factor receptor expression is abnormal in murine polycystic kidney. Kidney Int 1995;47, 490–499.

    CAS  PubMed  Google Scholar 

  128. Avner ED. Epithelial polarity and differentiation in polycystic kidney disease. J Cell Sci Suppl 1993;17, 217–222.

    CAS  PubMed  Google Scholar 

  129. Avner ED, Sweeney WE, Jr, Nelson WJ. Abnormal sodium pump distribution during renal tubulogenesis in congenital murine polycystic kidney disease. Proc Natl Acad Sci USA 1992;89, 7447–7451.

    CAS  PubMed  Google Scholar 

  130. Simons M, Gloy J, Ganner A et al. Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways. Nat Genet 2005;37, 537–543.

    CAS  PubMed  Google Scholar 

  131. Masyuk TV, Huang BQ, Masyuk AI et al. Biliary dysgenesis in the PCK rat, an orthologous model of autosomal recessive polycystic kidney disease. Am J Pathol 2004;165, 1719–1730.

    PubMed  Google Scholar 

  132. Masyuk AI, Masyuk TV, Splinter PL et al. Cholangiocyte cilia detect changes in luminal fluid flow and transmit them into intracellular Ca2+ and cAMP signaling. Gastroenterology 2006;131, 911–920.

    CAS  PubMed  Google Scholar 

  133. Masyuk AI, Gradilone SA, Banales JM et al. Cholangiocyte primary cilia are chemosensory organelles that detect biliary nucleotides via P2Y12 purinergic receptors. Am J Physiol Gastrointest Liver Physiol 2008;295, G725–G734.

    CAS  PubMed  Google Scholar 

  134. Banales JM, Masyuk TV, Bogert PS et al. Hepatic cystogenesis is associated with abnormal expression and location of ion transporters and water channels in an animal model of autosomal recessive polycystic kidney disease. Am J Pathol 2008;173, 1637–1646.

    CAS  PubMed  Google Scholar 

  135. Tietz PS, Marinelli RA, Chen XM et al. Agonist-induced coordinated trafficking of functionally related transport proteins for water and ions in cholangiocytes. J Biol Chem 2003;278, 20413–20419.

    CAS  PubMed  Google Scholar 

  136. Masyuk TV, Masyuk AI, Torres VE et al. Octreotide inhibits hepatic cystogenesis in a rodent model of polycystic liver disease by reducing cholangiocyte adenosine 3ʹ,5ʹ-cyclic monophosphate. Gastroenterology 2007;132, 1104–1116.

    CAS  PubMed  Google Scholar 

  137. Hogan MC, Torres VE. What the similarities of specific polycystic liver and kidney diseases can teach us about both. Nephrol News Issues 2008;22, 29–31.

    PubMed  Google Scholar 

  138. Sato Y, Harada K, Furubo S et al. Inhibition of intrahepatic bile duct dilation of the polycystic kidney rat with a novel tyrosine kinase inhibitor gefitinib. Am J Pathol 2006;169, 1238–1250.

    CAS  PubMed  Google Scholar 

  139. Shillingford JM, Murcia NS, Larson CH et al. The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc Natl Acad Sci USA 2006;103, 5466–5471.

    CAS  PubMed  Google Scholar 

  140. Tao Y, Kim J, Schrier RW, Edelstein CL. Rapamycin markedly slows disease progression in a rat model of polycystic kidney disease. J Am Soc Nephrol 2005;16, 46–51.

    CAS  PubMed  Google Scholar 

  141. Qian Q, Du H, King BF et al. Sirolimus reduces polycystic liver volume in ADPKD patients. J Am Soc Nephrol 2008;19, 631–638.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Medical Genetics Branch, Section on Human Biochemical Genetics, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    Maya Tuchman, William A. Gahl MD, PhD & Meral Gunay-Aygun MD

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  1. Maya Tuchman
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  2. William A. Gahl MD, PhD
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  3. Meral Gunay-Aygun MD
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  1. School of Medicine, Children's Hospital & Regional, University of Washington, Sand Point Way NE. 4800, Seattle, 98105, USA

    Karen F. Murray

  2. St. Paul University Hospital, Harry Hines Blvd. 5939, Dallas, 75390-9258, USA

    Anne M. Larson

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Tuchman, M., Gahl, W.A., Gunay-Aygun, M. (2010). Genetics of Fibrocystic Diseases of the Liver and Molecular Approaches to Therapy. In: Murray, K., Larson, A. (eds) Fibrocystic Diseases of the Liver. Clinical Gastroenterology. Humana Press. https://doi.org/10.1007/978-1-60327-524-8_4

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