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

Item Type:Article
Title:Heteroligomerization of an Aquaporin-2 mutant with wild-type Aquaporin-2 and their misrouting to late endosomes/lysosomes explains dominant nephrogenic diabetes insipidus
Creators Name:Marr, N. and Bichet, D.G. and Lonergan, M. and Arthus, M.F. and Jeck, N. and Seyberth, H.W. and Rosenthal, W. and van Os, C.H. and Oksche, A. and Deen, P.M.
Abstract: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 (727deltaG) in one AQP2 allele, which encoded an AQP2 mutant with an altered and extended C-terminal tail. When expressed in oocytes, the tetrameric AQP2-727deltaG was retained within the cell. When co-expressed, AQP2-727deltaG, 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, AQP2-727deltaG 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 AQP2-727deltaG mainly co-localized to late endosomes/lysosomes. In conclusion, hetero-oligomerization of AQP2-727deltaG 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.
Keywords:Amino Acid Sequence, Aquaporins, Base Sequence, Cell Membrane, Cultured Cells, Deamino Arginine Vasopressin, Nephrogenic Diabetes Insipidus, Endosomes, Immunohistochemistry, Kidney, Lysosomes, Molecular Sequence Data, Oocytes, Permeability, Point Mutation, Protein Transport, Renal Agents, Sequence Deletion, Water, Animals, Dogs
Source:Human Molecular Genetics
ISSN:0964-6906
Publisher:Oxford University Press (U.K.)
Volume:11
Number:7
Page Range:779-789
Date:2002
Official Publication:http://hmg.oxfordjournals.org/cgi/content/abstract/11/7/779
PubMed:View item in PubMed

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