Heteroligomerization of an Aquaporin-2 mutant with wild-type Aquaporin-2 and their misrouting to late endosomes/lysosomes explains dominant nephrogenic diabetes insipidus.
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.
Marr
Nannette
N
160 Department of Cell Physiology, Nijmegen Center of Molecular Life Sciences, University Medical Center St Radboud, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
Bichet
Daniel G
DG
Lonergan
Michele
M
Arthus
Marie-Francoise
MF
Jeck
Nikola
N
Seyberth
Hannsjörg W
HW
Rosenthal
Walter
W
van Os
Carel H
CH
Oksche
Alexander
A
Deen
Peter M T
PM
D000595:Amino Acid Sequence; D000818:Animals; D020346:Aquaporins / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology; D018500:Diabetes Insipidus, Nephrogenic / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D004285:Dogs; D011992:Endosomes / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D009865:Oocytes; D010539:Permeability; D017354:Point Mutation; D021381:Protein Transport / Q000235:genetics / Q000502:physiology; D012076:Renal Agents / Q000494:pharmacology; D017384:Sequence Deletion; D014867:Water / Q000378:metabolism
D020346:Aquaporins; D012076:Renal Agents; D014867:Water; D003894:Deamino Arginine Vasopressin