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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


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