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

Journal of Cell Biology - Tập 163 Số 5 - Trang 1099-1109 - 2003
Erik‐Jan Kamsteeg1, Daniel G. Bichet2, Irene B. M. Konings1, Hubert Nivet3, Michelle Lonergan2, Marie‐Françoise Arthus2, C.H. van Os1, Peter M.T. Deen1
11Department of Physiology, Nijmegen Center for Molecular Life Sciences, University Medical Center Nijmegen, Nijmegen 6500 HB, Netherlands
22Faculté de Médecine, Université de Montréal et Centre de Recherches, Hôpital du Sacre-Coeur de Montréal, H4J-1C5 Montréal, Quebec, Canada
33Département de Nephrology, Centre Hospitalier Universitaire de Tours, 37044 Tours, France

Tóm tắt

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.

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Journal of Cell Biology

Tập 163 Số 5

1099-1109

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