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Published 8 December 2003. doi:10.1083/jcb.200309017
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© The Rockefeller University Press, 0021-9525/2003/12/1099 $8.00
The Journal of Cell Biology, Volume 163, Number 5, 1099-1109

Article

Reversed polarized delivery of an aquaporin-2 mutant causes dominant nephrogenic diabetes insipidus



Erik-Jan Kamsteeg1, Daniel G. Bichet2, Irene B.M. Konings1, Hubert Nivet3, Michelle Lonergan2, Marie-Françoise Arthus2, Carel H. van Os1 and Peter M.T. Deen1

1 Department of Physiology, Nijmegen Center for Molecular Life Sciences, University Medical Center Nijmegen, Nijmegen 6500 HB, Netherlands
2 Faculté de Médecine, Université de Montréal et Centre de Recherches, Hôpital du Sacre-Coeur de Montréal, H4J-1C5 Montréal, Quebec, Canada
3 Département de Nephrology, Centre Hospitalier Universitaire de Tours, 37044 Tours, France

Address correspondence to P.M.T. Deen, Dept. of Physiology, Nijmegen Center for Molecular Life Sciences, University Medical Center Nijmegen, Research Tower, 7th Floor, Geert 30, PO Box 9101, Nijmegen 6500 HB, Netherlands. Tel.: 31-24-3617347. Fax: 31-24-3616413. email: p.deen{at}ncmls.kun.nl

Vasopressin regulates body water conservation by redistributing aquaporin-2 (AQP2) water channels from intracellular vesicles to the apical surface of renal collecting ducts, resulting in water reabsorption from urine. Mutations in AQP2 cause autosomal nephrogenic diabetes insipidus (NDI), a disease characterized by the inability to concentrate urine. Here, we report a frame-shift mutation in AQP2 causing dominant NDI. This AQP2 mutant is a functional water channel when expressed in Xenopus oocytes. However, expressed in polarized renal cells, it is misrouted to the basolateral instead of apical plasma membrane. Additionally, this mutant forms heterotetramers with wild-type AQP2 and redirects this complex to the basolateral surface. The frame shift induces a change in the COOH terminus of AQP2, creating both a leucine- and a tyrosine-based motif, which cause the reversed sorting of AQP2. Our data reveal a novel cellular phenotype in dominant NDI and show that dominance of basolateral sorting motifs in a mutant subunit can be the molecular basis for disease.

Key Words: aquaporin; water channel; dominant disease; hetero-oligomerization; missorting

Abbreviations used in this paper: AP, adaptor protein complex; AQP2, aquaporin-2; AVP, arginine vasopressin; CLSM, confocal laser-scanning microscopy; NDI, nephrogenic diabetes insipidus; Pf, osmotic water permeability; PKA, protein kinase A; wt, wild type.


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