Human Molecular Genetics Advance Access originally published online on August 12, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 20 2703-2710
DOI: 10.1093/hmg/ddg274
© 2003 Oxford University Press
Cellular and subcellular localization of the ARPKD protein; fibrocystin is expressed on primary cilia
1Division of Nephrology and 2Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA, 3Department of Medicine, Indiana University Medical Center, Indianapolis, IN, USA and 4Department of Nephrology, Fundació Puigvert, Barcelona, Spain
Received July 9, 2003; Accepted August 5, 2003
Autosomal recessive polycystic kidney disease (ARPKD) is an infantile form of PKD characterized by fusiform dilation of collecting ducts and congenital hepatic fibrosis. The ARPKD gene, PKHD1, is large (
470 kb; 67 exons) with a 12 222 bp longest open reading frame, although multiple different splice forms may be generated. The predicted full-length ARPKD protein, fibrocystin, is membrane bound with 4074 amino acids (447 kDa molecular weight). To characterize the pattern of fibrocystin expression we have generated four monoclonal antibodies (mAb) to the cytoplasmic tail of the protein. Western analysis of human kidney membrane protein showed an identical pattern with each mAb; a strongly expressing large product (>450 kDa), consistent with the predicted protein size, and a weaker 220 kDa band. The same large product was detected in rat and mouse kidney with lower level expression in liver. To further show that these mAbs recognize fibrocystin, tissue from ARPKD patients was analyzed and no fibrocystin products were detected. Immunohistochemical analysis of the developing kidney showed expression in the branching ureteric bud and collecting ducts, expression that persisted into adulthood. Biliary duct staining was found in the liver, plus staining in the pancreas and developing testis. Immunofluorescence analysis of MDCK cells showed a major site of expression in the primary cilia. Recent studies have associated the disease protein in various human and animal forms of PKD with cilia. The localization of fibrocystin to cilia further strengthens that correlation and indicates that the primary defect in ARPKD may be linked to ciliary dysfunction.
* To whom correspondence should be addressed at: 760 Stabile Building, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel: +1 5072660541; Fax: +1 5072669315; Email: harris.peter{at}mayo.edu
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|
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|
|
|
|
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|
|
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|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
C Bergmann, F Kupper, C P Schmitt, U Vester, T J Neuhaus, J Senderek, and K Zerres Multi-exon deletions of the PKHD1 gene cause autosomal recessive polycystic kidney disease (ARPKD) J. Med. Genet., October 1, 2005; 42(10): e63 - e63. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
M. M. Barr Caenorhabditis elegans as a Model to Study Renal Development and Disease: Sexy Cilia J. Am. Soc. Nephrol., February 1, 2005; 16(2): 305 - 312. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. J. Pazour Intraflagellar Transport and Cilia-Dependent Renal Disease: The Ciliary Hypothesis of Polycystic Kidney Disease J. Am. Soc. Nephrol., October 1, 2004; 15(10): 2528 - 2536. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Sun, A. Amsterdam, G. J. Pazour, D. G. Cole, M. S. Miller, and N. Hopkins A genetic screen in zebrafish identifies cilia genes as a principal cause of cystic kidney Development, August 15, 2004; 131(16): 4085 - 4093. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Zhang, P. D. Taulman, and B. K. Yoder Cystic Kidney Diseases: All Roads Lead to the Cilium Physiology, August 1, 2004; 19(4): 225 - 230. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Nurnberger, A. Kribben, A. O. Saez, G. Heusch, T. Philipp, and C. L. Phillips The Invs Gene Encodes a Microtubule-Associated Protein J. Am. Soc. Nephrol., July 1, 2004; 15(7): 1700 - 1710. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. Phillips, K. J. Miller, A. J. Filson, J. Nurnberger, J. L. Clendenon, G. W. Cook, K. W. Dunn, P. A. Overbeek, V. H. Gattone II, and R. L. Bacallao Renal Cysts of inv/inv Mice Resemble Early Infantile Nephronophthisis J. Am. Soc. Nephrol., July 1, 2004; 15(7): 1744 - 1755. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Wang, Y. Luo, P. D. Wilson, G. B. Witman, and J. Zhou The Autosomal Recessive Polycystic Kidney Disease Protein Is Localized to Primary Cilia, with Concentration in the Basal Body Area J. Am. Soc. Nephrol., March 1, 2004; 15(3): 592 - 602. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-Z. Zhang, W. Mai, C. Li, S.-y. Cho, C. Hao, G. Moeckel, R. Zhao, I. Kim, J. Wang, H. Xiong, et al. PKHD1 protein encoded by the gene for autosomal recessive polycystic kidney disease associates with basal bodies and primary cilia in renal epithelial cells PNAS, February 24, 2004; 101(8): 2311 - 2316. [Abstract] [Full Text] [PDF]
|
|