Uromodulin is expressed in renal primary cilia and UMOD mutations result in decreased ciliary uromodulin expression

Human Molecular Genetics

Volumn 19, Issue 10, 2010, Pages 1985-1997

  Zaucke, Frank ^a   Boehnlein, Joana M ^a   Steffens, Sarah ^a   Polishchuk, Roman S ^b   Rampoldi, Luca ^c   Fischer, Andreas ^b   Pasch, Andreas ^d   Boehm, Christoph W A ^a   Baasner, Anne ^a   Attanasio, Massimo ^e   Hoppe, Bernd ^a   Hopfer, Helmut ^f   Beck, Bodo B ^a   Sayer, John A ^g   Hildebrandt, Friedhelm ^e   Wolf, Matthias T F ^a,h  

^a UNIVERSITY HOSPITAL OF COLOGNE   (Germany)

^b University of Cologne ^*  (Switzerland)

^c DULBECCO TELETHON INSTITUTE   (Italy)

^d UNIVERSITY OF BERN   (Switzerland)

^e UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

^f UNIVERSITY HOSPITAL BASEL   (Switzerland)

^g NEWCASTLE UNIVERSITY   (United Kingdom)

^h UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

KINESIN; TAMM HORSFALL GLYCOPROTEIN;

ARTICLE; CELL CULTURE; CONTROLLED STUDY; ELECTRON MICROSCOPY; EUKARYOTIC FLAGELLUM; GENE MUTATION; GENETIC ANALYSIS; GENETIC TRANSFECTION; HUMAN; HUMAN TISSUE; IMMUNOBLOTTING; IMMUNOELECTRON MICROSCOPY; IMMUNOFLUORESCENCE; KIDNEY BIOPSY; KIDNEY TUBULE; MAJOR CLINICAL STUDY; MEDULLARY SPONGE KIDNEY; PATHOGENESIS; PATHOPHYSIOLOGY; POLYACRYLAMIDE GEL ELECTROPHORESIS; PRIORITY JOURNAL; PROTEIN LOCALIZATION;

ADAPTOR PROTEINS, SIGNAL TRANSDUCING; ADOLESCENT; ADULT; ANIMALS; ANTIBODIES; BIOPSY; BLOTTING, WESTERN; CELL DIVISION; CELLS, CULTURED; CHILD; CILIA; FLUORESCENT ANTIBODY TECHNIQUE; HUMANS; KIDNEY; KINESIN; MEMBRANE PROTEINS; MICE; MIDDLE AGED; MUCOPROTEINS; MUTANT PROTEINS; MUTATION; PROTEIN TRANSPORT; TRANSFECTION; YOUNG ADULT;

EID: 77952478220     PISSN: 09646906     EISSN: 14602083     Source Type: Journal    
DOI: 10.1093/hmg/ddq077     Document Type: Article

References (62)

1. Hart, T.C., Gorry, M.C., Hart, P.S., Woodard, A.S., Shihabi, Z., Sandhu, J., Shirts, B., Xu, L., Zhu, H., Barmada, M.M. et al. (2002) Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy. J. Med. Genet., 39, 882-892.
2. Dahan, K., Devuyst, O., Smaers, M., Vertommen, D., Loute, G., Poux, J.M., Viron, B., Jacquot, C., Gagnadoux, M.F., Chauveau, D. et al. (2003) A cluster of mutations in the UMOD gene causes familial juvenile hyperuricemic nephropathy with abnormal expression of Uromodulin. J. Am. Soc. Nephrol., 14, 2883-2893.
3. Rampoldi, L., Caridi, G., Santon, D., Boaretto, F., Bernascone, I., Lamorte, G., Tardanico, R., Dagnino, M., Colussi, G., Scolari, F. et al. (2003) Allelism of MCKD, FJHN, and GCKD caused by impairment of uromodulin export dynamics. Hum. Mol. Genet., 12, 3369-3384.
4. Waldherr, R., Lennert, T., Weber, H.P., Födisch, H.J. and Schärer, K. (1982) The nephronophthisis complex. A clinicopathologic study in children. Virchows. Arch. A. Pathol. Anat. Histol., 394, 235-254.
5. Hildebrandt, F. and Otto, E. (2000) Molecular genetics of nephronophthisis and medullary cystic kidney disease. J. Am. Soc. Nephrol., 11, 1753-1761.
6. Hildebrandt, F. and Zhou, W. (2007) Nephronophthisis-associated ciliopathies. J. Am. Soc. Nephrol., 18, 1855-1871.
7. McBride, M.B., Rigden, S., Haycock, G.B., Dalton, N., Van't Hoff, W., Rees, L., Raman, G.V., Moro, F., Ogg, C.S., Cameron, J.S. et al. (1998) Presymptomatic detection of familial juvenile hyperuricaemic nephropathy in children. Pediatr. Nephrol., 12, 357-364.
8. Bleyer, A.J., Woodard, A.S., Shihabi, Z., Sandhu, J., Zhu, H., Satko, S.G., Weller, N., Deterding, E., McBride, D., Gorry, M.C. et al. (2003) Clinical characterization of a family with a mutation in the uromodulin (Tamm-Horsfall glycoprotein) gene. Kidney Int., 64, 36-42.
9. Vylet'al, P., Kublová, M., Kalbácová, M., Hodanová, K., Baresová, V., Stibůrková, B., Sikora, J., Hůlková, H., Zivný, J., Majewski, J. et al. (2006) Alterations of uromodulin biology: a common denominator of the genetically heterogeneous FJHN/MCKD syndrome. Kidney Int., 70, 1155-1169.
10. Wolf, M.T., Beck, B.B., Zaucke, F., Kunze, A., Misselwitz, J., Ruley, J., Ronda, T., Fischer, A., Eifinger, F., Licht, C. et al. (2007) The Uromodulin C744G mutation causes MCKD2 and FJHN in children and adults and may be due to a possible founder effect. Kidney Int., 71, 574-581.
11. Wolf, M.T., Mucha, B.E., Attanasio, M., Zalewski, I., Karle, S.M., Neumann, H.P., Rahman, N., Bader, B., Baldamus, C.A., Otto, E. et al. (2003) Mutations of the Uromodulin gene in MCKD type 2 patients cluster in exon 4 which encodes three EGF-like domains. Kidney Int., 64, 1580-1587.
12. Williams, S.E., Reed, A.A., Galvanovskis, J., Antignac, C., Goodship, T., Karet, F.E., Kotanko, P., Lhotta, K., Morinière, V., Williams, P. et al. (2009) Uromodulin mutations causing familial juvenile hyperuricaemic nephropathy lead to protein maturation defects and retention in the endoplasmic reticulum. Hum. Mol. Genet., 18, 2963-2974.
13. Bernascone, I., Vavassori, S., Di Pentima, A., Santambrogio, S., Lamorte, G., Amoroso, A., Scolari, F., Ghiggeri, G.M., Casari, G., Polishchuk, R. et al. (2006) Defective intracellular trafficking of uromodulin mutant isoforms. Traffic, 7, 1567-1579.
14. Choi, S.W., Ryu, O.H., Choi, S.J., Song, I.S., Bleyer, A.J. and Hart, T.C. (2005) Mutant tamm-horsfall glycoprotein accumulation in endoplasmic reticulum induces apoptosis reversed by colchicine and sodium 4-phenylbutyrate. J. Am. Soc. Nephrol., 16, 3006-3014.
15. Rindler, M.J., Naik, S.S., Li, N., Hoops, T.C. and Peraldi, M.N. (1990) Uromodulin (Tamm-Horsfall glycoprotein/uromucoid) is a phosphatidylinositol-linked membrane protein. J. Biol. Chem., 265, 20784-20789.
16. Santambrogio, S., Cattaneo, A., Bernascone, I., Schwend, T., Jovine, L., Bachi, A. and Rampoldi, L. (2008) Urinary uromodulin carries an intact ZP domain generated by a conserved C-terminal proteolytic cleavage. Biochem. Biophys. Res. Commun., 370, 410-413.
17. Tamm, I. and Horsfall, F.L. Jr. (1950) Characterization and separation of an inhibitor of viral hemagglutination present in urine. Proc. Soc. Exp. Biol. Med., 74, 106-108.
18. Pak, J., Pu, Y., Zhang, Z.T., Hasty, D.L. and Wu, X.R. (2001) Tamm-Horsfall protein binds to type 1 fimbriated Escherichia coli and prevents E. coli from binding to uroplakin Ia and Ib receptors. J. Biol. Chem., 276, 9924-9930.
19. Leeker, A., Kreft, B., Sandmann, J., Bates, J., Wasenauer, G., Múller, H., Sack, K. and Kumar, S. (1997) Tamm-Horsfall protein inhibits binding of S- and P- fimbriated Escherichia coli to human renal tubular epithelial cells. Exp. Nephrol., 5, 38-46.
20. Rhodes, D.C.J. (2002) Binding of Tamm-Horsfall protein to complement 1q and complement 1, including influence of hydrogen-ion concentration. Immunol. Cell. Biol., 78, 558-566.
21. Ying, W.Z. and Sanders, P.W. (2001) Mapping the binding domain of immunoglobulin light chains for Tamm-Horsfall protein. Am. J. Pathol., 158, 1859-1866.
22. Marengo, S.R., Chen, D.H., Kaung, H.L., Resnick, M.I. and Yang, L. (2002) Decreased renal expression of the putative calcium oxalate inhibitor Tamm-Horsfall protein in the ethylene glycol rat model of calcium oxalate urolithiasis. J. Urol., 167, 22192-22197.
23. Bates, J.M., Raffi, H.M., Prasadan, K., Mascarenhas, R., Laszik, Z., Maeda, N., Hultgren, S.J. and Kumar, S. (2004) Tamm-Horsfall protein knockout mice are more prone to urinary tract infection: rapid communication. Kidney Int., 65, 791-797.
24. Kemter, E., Rathkolb, B., Rozman, J., Hans, W., Schrewe, A., Landbrecht, C., Klaften, M., Ivandic, B.T., Fuchs, H., Gailus-Durner, V. et al. (2009) Novel missense mutation of uromodulin in mice causes renal dysfunction with alterations in urea handling, energy and bone metabolism. Am. J. Physiol. Renal. Physiol., 297, F1391-F1398.
25. Köttgen, A., Glazer, N.L., Dehghan, A., Hwang, S.J., Katz, R., Li, M., Yang, Q., Gudnason, V., Launer, L.J., Harris, T.B. et al. (2009) Multiple loci associated with indices of renal function and chronic kidney disease. Nat. Genet., 41, 712-717.
26. Wu, T.H., Hsieh, S.C., Yu, C.Y., Lee, Y.F., Tsai, C.Y. and Yu, C.L. (2008) Intact protein core structure is essential for protein-binding, mononuclear cell proliferating, and neutrophil phagocytosis-enhancing activities of normal human urinary Tamm-Horsfall glycoprotein. Int. Immunopharmacol., 8, 90-99.
27. Muchmore, A.V. and Decker, J.M. (1987) Evidence that recombinant IL 1 alpha exhibits lectin-like specificity and binds to homogeneous uromodulin via N-linked oligosaccharides. J. Immunol., 138, 2541-2546.
28. Sherblom, A.P., Decker, J.M. and Muchmore, A.V. (1988) The lectin-like interaction between recombinant tumor necrosis factor and uromodulin. J. Biol. Chem., 263, 5418-5424.
29. Rhodes, D.C., Hinsman, E.J. and Rhodes, J.A. (1993) Tamm-Horsfall glycoprotein binds IgG with high affinity. Kidney Int., 44, 1014-1021.
30. Thomas, D.B., Davies, M., Peters, J.R. and Williams, J.D. (1993) Tamm Horsfall protein binds to a single class of carbohydrate specific receptors on human neutrophils. Kidney Int., 44, 423-429.
31. Wimmer, T., Cohen, G., Saemann, M.D. and Hörl, W.H. (2004) Effects of Tamm-Horsfall protein on polymorphonuclear leukocyte function. Nephrol. Dial. Transplant., 19, 2192-2197.
32. Yu, C.L., Lin, W.M., Liao, T.S., Tsai, C.Y., Sun, K.H. and Chen, K.H. (1992) Tamm-Horsfall glycoprotein (THG) purified from normal human pregnancy urine increases phagocytosis, complement receptor expressions and arachidonic acid metabolism of polymorphonuclear neutrophils. Immunopharmacology, 24, 181-190.
33. Säemann, M.D., Weichhart, T., Zeyda, M., Staffler, G., Schunn, M., Stuhlmeier, K.M., Sobanov, Y., Stulnig, T.M., Akira, S., von Gabain, A. et al. (2005) Tamm-Horsfall glycoprotein links innate immune cell activation with adaptive immunity via a Toll-like receptor-4-dependent mechanism. J. Clin. Invest., 115, 468-475.
34. Mattey, M. and Naftalin, L. (1992) Mechanoelectrical transduction, ion movement and water stasis in uromodulin. Experientia, 48, 975-980.
35. Hildebrandt, F. and Otto, E. (2005) Cilia and centrosomes: a unifying pathogenic concept for cystic kidney disease? Nat. Rev. Genet., 6, 928-940.
36. Yoder, B.K., Hou, X. and Guay-Woodford, L.M. (2002) The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia. J. Am. Soc. Nephrol., 13, 2508-2516.
37. Menezes, L.F., Cai, Y., Nagasawa, Y., Silva, A.M., Watkins, M.L., Da Silva, A.M., Somlo, S., Guay-Woodford, L.M., Germino, G.G. and Onuchic, L.F. (2004) Polyductin, the PKHD1 gene product, comprises isoforms expressed in plasma membrane, primary cilium, and cytoplasm. Kidney Int., 66, 1345-1355.
38. Tobin, J.L. and Beales, P.L. (2007) Bardet-Biedl syndrome: beyond the cilium. Pediatr. Nephrol., 22, 926-936.
39. Brown, N.E. and Murcia, N.S. (2003) Delayed cystogenesis and increased ciliogenesis associated with the re-expression of polaris in Tg737 mutant mice. Kidney Int., 63, 1220-1229.
40. Hou, X., Mrug, M., Yoder, B.K., Lefkowitz, E.J., Kremmidiotis, G., D'Eustachio, P., Beier, D.R. and Guay-Woodford, L.M. (2002) Cystin, a novel cilia-associated protein, is disrupted in the cpk mouse model of polycystic kidney disease. J. Clin. Invest., 109, 533-540.
41. Morgan, D., Turnpenny, L., Goodship, J., Dai, W., Majumder, K., Matthews, L., Gardner, A., Schuster, G., Vien, L., Harrison, W. et al. (1998) Inversin, a novel gene in the vertebrate left-right axis pathway, is partially deleted in the inv mouse. Nat. Genet., 20, 149-156.
42. Liu, S., Lu, W., Obara, T., Kuida, S., Lehoczky, J., Dewar, K., Drummond, I.A. and Beier, D.R. (2002) A defect in a novel Nek-family kinase causes cystic kidney disease in the mouse and in zebrafish. Development, 129, 5839-5846.
43. Gresh, L., Fischer, E., Reimann, A., Tanguy, M., Garbay, S., Shao, X., Hiesberger, T., Fiette, L., Igarashi, P., Yaniv, M. et al. (2004) A transcriptional network in polycystic kidney disease. EMBO J., 23, 1657-1668.
44. Mollet, G., Silbermann, F., Delous, M., Salomon, R., Antignac, C. and Saunier, S. (2005) Characterization of the nephrocystin/nephrocystin-4 complex and subcellular localization of nephrocystin-4 to primary cilia and centrosomes. Hum. Mol. Genet., 14, 645-656.
45. Sayer, J.A., Otto, E.A., O'Toole, J.F., Nurnberg, G., Kennedy, M.A., Becker, C., Hennies, H.C., Helou, J., Attanasio, M., Fausett, B.V. et al. (2006) The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nat. Genet., 38, 674-681.
46. Delous, M., Baala, L., Salomon, R., Laclef, C., Vierkotten, J., Tory, K., Golzio, C., Lacoste, T., Besse, L., Ozilou, C. et al. (2007) The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nat. Genet., 39, 875-881.
47. Morgan, D., Eley, L., Sayer, J., Strachan, T., Yates, L.M., Craighead, A.S. and Goodship, J.A. (2002) Expression analyses and interaction with the anaphase promoting complex protein Apc2 suggest a role for inversin in primary cilia and involvement in the cell cycle. Hum. Mol. Genet., 11, 3345-3350.
48. Otto, E.A., Trapp, M.L., Schultheiss, U.T., Helou, J., Quarmby, L.M. and Hildebrandt, F. (2008) NEK8 mutations affect ciliary and centrosomal localization and may cause nephronophthisis. J. Am. Soc. Nephrol., 19, 587-592.
49. Benzing, T., Gerke, P., Höpker, K., Hildebrandt, F., Kim, E. and Walz, G. (2001) Nephrocystin interacts with Pyk2, p130(Cas), and tensin and triggers phosphorylation of Pyk2. Proc. Natl Acad. Sci. USA., 98, 9784-9789.
50. Wu, Y., Dai, X.Q., Li, Q., Chen, C.X., Mai, W., Hussain, Z., Long, W., Montalbetti, N., Li, G., Glynne, R. et al. (2006) Kinesin-2 mediates physical and functional interactions between polycystin-2 and fibrocystin. Hum. Mol. Genet., 15, 3280-3292.
51. Geng, L., Okuhara, D., Yu, Z., Tian, X., Cai, Y., Shibazaki, S. and Somlo, S. (2006) Polycystin-2 traffics to cilia independently of polycystin-1 by using an N-terminal RVxP motif. J. Cell. Sci., 119, 1383-1395.
52. Berbari, N.F., Johnson, A.D., Lewis, J.S., Askwith, C.C. and Mykytyn, K. (2008) Identification of ciliary localization sequences within the third intracellular loop of G-protein-coupled receptors. Mol. Biol. Cell., 19, 1540-1547.
53. Kaimori, J.Y., Nagasawa, Y., Menezes, L.F., Garcia-Gonzalez, M.A., Deng, J., Imai, E., Onuchic, L.F., Guay-Woodford, L.M. and Germino, G.G. (2007) Polyductin undergoes notch-like processing and regulated release from primary cilia. Hum. Mol. Genet., 16, 942-956.
54. Hiesberger, T., Gourley, E., Erickson, A., Koulen, P., Ward, C.J., Masyuk, T.V., Larusso, N.F., Harris, P.C. and Igarashi, P. (2006) Proteolytic cleavage and nuclear translocation of fibrocystin is regulated by intracellular Ca2+ and activation of protein kinase C. J. Biol. Chem., 281, 34357-34364.
55. Nauli, S.M., Alenghat, F.J., Luo, Y., Williams, E., Vassilev, P., Li, X., Elia, A.E., Lu, W., Brown, E.M., Quinn, S.J. et al. (2003) Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat. Genet., 33, 129-137.
56. Fischer, E., Legue, E., Doyen, A., Nato, F., Nicolas, J.F., Torres, V., Yaniv, M. and Pontoglio, M. (2006) Defective planar cell polarity in polycystic kidney disease. Nat. Genet., 38, 21-53.
57. Simons, M., Gloy, J., Ganner, A., Bullerkotte, A., Bashkurov, M., Krönig, C., Schermer, B., Benzing, T., Cabello, O.A., Jenny, A. et al. (2005) Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways. Nat. Genet., 37, 537-543.
58. Corbit, K.C., Shyer, A.E., Dowdle, W.E., Gaulden, J., Singla, V., Chen, M.H., Chuang, P.T. and Reiter, J.F. (2008) Kif3a constrains beta-catenin-dependent Wnt signalling through dual ciliary and non-ciliary mechanisms. Nat. Cell. Biol., 10, 70-76.
59. Patel, V., Li, L., Cobo-Stark, P., Shao, X., Somlo, S., Lin, F. and Igarashi, P. (2008) Acute kidney injury and aberrant planar cell polarity induce cyst formation in mice lacking renal cilia. Hum. Mol. Genet., 17, 1578-1590.
60. Hamada, T., Ichida, K., Hosoyamada, M., Mizuta, E., Yanagihara, K., Sonoyama, K., Sugihara, S., Igawa, O., Hosoya, T., Ohtahara, A. et al. (2008) Uricosuric action of losartan via the inhibition of urate transporter 1 (URAT 1) in hypertensive patients. Am. J. Hypertens., 21, 1157-1162.
61. Wilcox, W.D. (1996) Abnormal serum uric acid levels in children. J. Pediatr., 128, 731-741.
62. Polishchuk, E.V., Di Pentima, A., Luini, A. and Polishchuk, R.S. (2003) Mechanism of constitutive export from the golgi: bulk flow via the formation, protrusion, and en bloc cleavage of large trans-golgi network tubular domains. Mol. Biol. Cell., 14, 4470-4485.