Skip Navigation

This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (53)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Marr, N.
Right arrow Articles by Deen, P. M. T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Marr, N.
Right arrow Articles by Deen, P. M. T.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Human Molecular Genetics, 2002, Vol. 11, No. 7 779-789
© 2002 Oxford University Press

Heteroligomerization of an Aquaporin-2 mutant with wild-type Aquaporin-2 and their misrouting to late endosomes/lysosomes explains dominant nephrogenic diabetes insipidus

Nannette Marr, Daniel G Bichet1, Michele Lonergan1, Marie-Francoise Arthus1, Nikola Jeck2, Hannsjörg W. Seyberth2, Walter Rosenthal4, Carel H. van Os, Alexander Oksche3 and Peter M. T. Deen+

160 Department of Cell Physiology, Nijmegen Center of Molecular Life Sciences, University Medical Center St Radboud, PO Box 9101, 6500 HB Nijmegen, The Netherlands, 1Department of Medicine, University of Montreal and Centre de Recherches, Hôpital du Sacre-Coeur de Montreal, Montreal, Quebec, Canada, 2Universitätskinderklinik, 35033 Marburg, Germany, 3Forschungsinstitut für Molekulare Pharmakologie, 13125 Berlin, Germany and 4Institut für Pharmakologie, 14195 Berlin, Germany

Autosomal nephrogenic diabetes insipidus (NDI), a disease in which the kidney is unable to concentrate urine in response to vasopressin, is caused by mutations in the Aquaporin-2 (AQP2) gene. Analysis of a new family with dominant NDI revealed a single nucleotide deletion (727{Delta}G) in one AQP2 allele, which encoded an AQP2 mutant with an altered and extended C-terminal tail. When expressed in oocytes, the tetrameric AQP2–727{Delta}G was retained within the cell. When co-expressed, AQP2–727{Delta}G, but not a mutant in recessive NDI (AQP2–R187C), formed hetero-oligomers with wild-type (wt) AQP2 and reduced the water permeability of these oocytes, because of a reduced plasma membrane expression of wt-AQP2. Expressed in renal epithelial cells, AQP2–727{Delta}G predominantly localized to the basolateral membrane and late endosomes/lysosomes, whereas wt-AQP2 was expressed in the apical membrane. Upon co-expressing in these cells, wt-AQP2 and AQP2–727{Delta}G mainly co-localized to late endosomes/lysosomes. In conclusion, hetero-oligomerization of AQP2–727{Delta}G with wt-AQP2 and consequent mistargeting of this complex to late endosomes/lysosomes results in absence of AQP2 in the apical membrane, which can explain dominant NDI in this family. Together with other mutants in dominant NDI, our data reveal that a misrouting, instead of a lack of function, is a general mechanism for the ‘loss of function’ phenotype in dominant NDI and visualizes for the first time a mislocalization of a wild-type protein to late endosomes/lysosomes in polarized cells after oligomerization with a mutant protein.

+ To whom correspondence should be addressed. Tel: +31 24 361 7347; Fax: +31 24 361 6413; Email: peterd@sci.kun.nl


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Hum Mol GenetHome page
M. D. Sorani, Z. Zador, E. Hurowitz, D. Yan, K. M. Giacomini, and G. T. Manley
Novel variants in human Aquaporin-4 reduce cellular water permeability
Hum. Mol. Genet., August 1, 2008; 17(15): 2379 - 2389.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. Rev.Home page
D. N. Hebert and M. Molinari
In and Out of the ER: Protein Folding, Quality Control, Degradation, and Related Human Diseases
Physiol Rev, October 1, 2007; 87(4): 1377 - 1408.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
P. P. Shi, X. R. Cao, J. Qu, K. A. Volk, P. Kirby, R. A. Williamson, J. B. Stokes, and B. Yang
Nephrogenic diabetes insipidus in mice caused by deleting COOH-terminal tail of aquaporin-2
Am J Physiol Renal Physiol, May 1, 2007; 292(5): F1334 - F1344.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
P. M. T. Deen
Mouse models for congenital nephrogenic diabetes insipidus: what can we learn from them?
Nephrol. Dial. Transplant., April 1, 2007; 22(4): 1023 - 1026.
[Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
E. Sohara, T. Rai, S.-S. Yang, K. Uchida, K. Nitta, S. Horita, M. Ohno, A. Harada, S. Sasaki, and S. Uchida
Pathogenesis and treatment of autosomal-dominant nephrogenic diabetes insipidus caused by an aquaporin 2 mutation
PNAS, September 19, 2006; 103(38): 14217 - 14222.
[Abstract] [Full Text] [PDF]

Home page
 J. Cell Sci.Home page
D. Ito, I. Koshino, N. Arashiki, H. Adachi, M. Tomihari, S. Tamahara, K. Kurogi, T. Amano, K.-i. Ono, and M. Inaba
Ubiquitylation-independent ER-associated degradation of an AE1 mutant associated with dominant hereditary spherocytosis in cattle
J. Cell Sci., September 1, 2006; 119(17): 3602 - 3612.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
J. H. Robben, N. V. A. M. Knoers, and P. M. T. Deen
Cell biological aspects of the vasopressin type-2 receptor and aquaporin 2 water channel in nephrogenic diabetes insipidus.
Am J Physiol Renal Physiol, August 1, 2006; 291(2): F257 - F270.
[Abstract] [Full Text] [PDF]

Home page
 ANN INTERN MEDHome page
J. M. Sands and D. G. Bichet
Nephrogenic Diabetes Insipidus
Ann Intern Med, February 7, 2006; 144(3): 186 - 194.
[Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
T. M. Fujiwara and D. G. Bichet
Molecular Biology of Hereditary Diabetes Insipidus
J. Am. Soc. Nephrol., October 1, 2005; 16(10): 2836 - 2846.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
F. de Mattia, P. J.M. Savelkoul, E.-J. Kamsteeg, I. B.M. Konings, P. van der Sluijs, R. Mallmann, A. Oksche, and P. M.T. Deen
Lack of Arginine Vasopressin-Induced Phosphorylation of Aquaporin-2 Mutant AQP2-R254L Explains Dominant Nephrogenic Diabetes Insipidus
J. Am. Soc. Nephrol., October 1, 2005; 16(10): 2872 - 2880.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
F. de Mattia, P. J.M. Savelkoul, D. G. Bichet, E.-J. Kamsteeg, I. B.M. Konings, N. Marr, M.-F. Arthus, M. Lonergan, C. H. van Os, P. van der Sluijs, et al.
A novel mechanism in recessive nephrogenic diabetes insipidus: wild-type aquaporin-2 rescues the apical membrane expression of intracellularly retained AQP2-P262L
Hum. Mol. Genet., December 15, 2004; 13(24): 3045 - 3056.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Cell Physiol.Home page
M. Greenough, L. Pase, I. Voskoboinik, M. J. Petris, A. W. O'Brien, and J. Camakaris
Signals regulating trafficking of Menkes (MNK; ATP7A) copper-translocating P-type ATPase in polarized MDCK cells
Am J Physiol Cell Physiol, November 1, 2004; 287(5): C1463 - C1471.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
Y. Tajika, T. Matsuzaki, T. Suzuki, T. Aoki, H. Hagiwara, M. Kuwahara, S. Sasaki, and K. Takata
Aquaporin-2 Is Retrieved to the Apical Storage Compartment via Early Endosomes and Phosphatidylinositol 3-Kinase-Dependent Pathway
Endocrinology, September 1, 2004; 145(9): 4375 - 4383.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
Q. Gong, C. L. Anderson, C. T. January, and Z. Zhou
Pharmacological rescue of trafficking defective HERG channels formed by coassembly of wild-type and long QT mutant N470D subunits
Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H652 - H658.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
M. A.J. Devonald and F. E. Karet
Renal Epithelial Traffic Jams and One-Way Streets
J. Am. Soc. Nephrol., June 1, 2004; 15(6): 1370 - 1381.
[Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
C. Boccalandro, F. de Mattia, D.-C. Guo, L. Xue, P. Orlander, T. M. King, P. Gupta, P. M.T. Deen, V. R Lavis, and D. M. Milewicz
Characterization of an Aquaporin-2 Water Channel Gene Mutation Causing Partial Nephrogenic Diabetes Insipidus in a Mexican Family: Evidence of Increased Frequency of the Mutation in the Town of Origin
J. Am. Soc. Nephrol., May 1, 2004; 15(5): 1223 - 1231.
[Abstract] [Full Text] [PDF]

Home page
 J. Cell Sci.Home page
A. M. Toye, G. Banting, and M. J. A. Tanner
Regions of human kidney anion exchanger 1 (kAE1) required for basolateral targeting of kAE1 in polarised kidney cells: mis-targeting explains dominant renal tubular acidosis (dRTA)
J. Cell Sci., March 15, 2004; 117(8): 1399 - 1410.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Cell Physiol.Home page
B. W. M. van Balkom, M. P. J. Graat, M. van Raak, E. Hofman, P. van der Sluijs, and P. M. T. Deen
Role of cytoplasmic termini in sorting and shuttling of the aquaporin-2 water channel
Am J Physiol Cell Physiol, February 1, 2004; 286(2): C372 - C379.
[Abstract] [Full Text]

Home page
 J. Biol. Chem.Home page
G. Hendriks, M. Koudijs, B. W. M. van Balkom, V. Oorschot, J. Klumperman, P. M. T. Deen, and P. van der Sluijs
Glycosylation Is Important for Cell Surface Expression of the Water Channel Aquaporin-2 but Is Not Essential for Tetramerization in the Endoplasmic Reticulum
J. Biol. Chem., January 23, 2004; 279(4): 2975 - 2983.
[Abstract] [Full Text] [PDF]

Home page
 J. Cell Biol.Home page
E.-J. Kamsteeg, D. G. Bichet, I. B.M. Konings, H. Nivet, M. Lonergan, M.-F. Arthus, C. H. van Os, and P. M.T. Deen
Reversed polarized delivery of an aquaporin-2 mutant causes dominant nephrogenic diabetes insipidus
J. Cell Biol., December 8, 2003; 163(5): 1099 - 1109.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
K. Hirano, C. Zuber, J. Roth, and M. Ziak
The Proteasome Is Involved in the Degradation of Different Aquaporin-2 Mutants Causing Nephrogenic Diabetes Insipidus
Am. J. Pathol., July 1, 2003; 163(1): 111 - 120.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
D. Brown
The ins and outs of aquaporin-2 trafficking
Am J Physiol Renal Physiol, May 1, 2003; 284(5): F893 - F901.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
B. W. M. van Balkom, M. van Raak, S. Breton, N. Pastor-Soler, R. Bouley, P. van der Sluijs, D. Brown, and P. M. T. Deen
Hypertonicity Is Involved in Redirecting the Aquaporin-2 Water Channel into the Basolateral, Instead of the Apical, Plasma Membrane of Renal Epithelial Cells
J. Biol. Chem., January 3, 2003; 278(2): 1101 - 1107.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
B. W. M. van Balkom, P. J. M. Savelkoul, D. Markovich, E. Hofman, S. Nielsen, P. van der Sluijs, and P. M. T. Deen
The Role of Putative Phosphorylation Sites in the Targeting and Shuttling of the Aquaporin-2 Water Channel
J. Biol. Chem., October 25, 2002; 277(44): 41473 - 41479.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
N. Marr, D. G. Bichet, S. Hoefs, P. J. M. Savelkoul, I. B. M. Konings, F. de Mattia, M. P. J. Graat, M.-F. Arthus, M. Lonergan, T. M. Fujiwara, et al.
Cell-Biologic and Functional Analyses of Five New Aquaporin-2 Missense Mutations that Cause Recessive Nephrogenic Diabetes Insipidus
J. Am. Soc. Nephrol., September 1, 2002; 13(9): 2267 - 2277.
[Abstract] [Full Text] [PDF]


Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.